System and method for determining reentrant ventricular tachycardia isthmus location and shape for catheter ablation

ABSTRACT

A method and system for identifying and localizing a reentrant circuit isthmus in a heart of a subject during sinus rhythm is provided. The method may include (a) receiving electrogram signals from the heart during sinus rhythm via electrodes, (b) creating a map based on the electrogram signals, (c) determining, based on the map, a location of the reentrant circuit isthmus in the heart, and (d) displaying the location of the reentrant circuit isthmus.

The invention of the present disclosure was made from Government supportunder Grant HL-31393 and Project Grant HL-30557 from the Heart, Lung andBlood Institutes, National Institutes of Health, a Research Grant fromthe Whitaker Foundation, and the American Heart Association EstablishedInvestigator Award. Accordingly, the U.S. Government has certain rightsto this invention.

This application is a §371 national stage of PCT/US02/24130, filed Jul.30, 2002, a continuation-in-part of U.S. application Ser. No.09/918,216, filed Jul. 30, 2001, now U.S. Pat. No. 6,847,839 B2, issuedJan. 25, 2005, the contents of all of which are hereby incorporated byreference.

Throughout this disclosure, various publications may be referenced byArabic numerals in brackets. Disclosures of these publications in theirentireties are hereby incorporated by reference into this application tomore fully describe the state of the art to which this disclosurepertains. Full citations of these publications may be found at the endof the specification.

BACKGROUND

In canine hearts with inducible reentry, the isthmus tends to form alongan axis from the area of last to first activity during sinus rhythm. Itwas hypothesized that this phenomenon could be quantified to predictreentry and the isthmus location. An in situ canine model of reentrantventricular tachycardia occurring in the epicardial border zone was usedin 54 experiments (25 canine hearts in which primarily long monomorphicruns of figure-8 reentry was inducible, 11 with short monomorphic orpolymorphic runs, and 18 lacking inducible reentry). From the sinusrhythm activation map for each experiment, the linear regressioncoefficient and slope was calculated for the activation times along eachof 8 rays extending from the area of last-activation. The slope of theregression line for the ray with greatest regression coefficient (calledthe primary axis) was used to predict whether or not reentry would beinducible (correct prediction in 48/54 experiments). For all 36experiments with reentry, isthmus location and shape were then estimatedbased on site-to-site differences in sinus rhythm electrogram duration.For long and short-runs of reentry, estimated isthmus location and shapepartially overlapped the actual isthmus (mean overlap of 71.3% and43.6%, respectively). On average for all reentry experiments, a linearablation lesion positioned across the estimated isthmus would havespanned 78.2% of the actual isthmus width. Parameters of sinus rhythmactivation provide key information for prediction of reentryinducibility, and isthmus location and shape.

During ventricular tachycardia, the heart beats rapidly which can bedebilitating to the patient and cause such things as tiredness and evensyncope (i.e. fainting). This clinical problem usually follows amyocardial infarction (heart attack) and is caused by abnormalelectrical conduction in the heart because the cells become damagedduring the infarct. When conduction is slow and abnormal, a processcalled reentry can occur in which the propagating electrical wavefronttravels in a circle, or double loop, and reenters the area where it hadpreviously traveled. This propagation around the loop(s) occurs veryrapidly, and a heartbeat occurs once each time the propagating wavefronttraverses around the loop or loops. Since the condition is abnormal, theheart muscle does not contract as it should, so that the strength of thepumping action is reduced, and the rapidity of the heartbeat causes theheart chambers to not fill with blood completely. Therefore, because ofboth the poor filling action and the poor pumping action, there is lessblood delivered to the tissues. This causes the maladies that thepatient experiences.

A promising cure for this ailment is radio-frequency catheter ablation,which does not require surgery and is permanent. In the ablationprocedure, a catheter is inserted through an artery of the patient andis positioned in the heart chamber. At the appropriate location on theinner heart surface, known as the endocardium, radio-frequency energy isdelivered from the tip of the catheter to the heart tissue, therebyblocking conduction at the place of delivery of the energy, which iscalled the target site on the heart. Ideally, energy is delivered to thelocation between the double loop where the electrical wavefrontpropagates. This is called the best, or optimal target site. However, itis sometimes difficult to locate the best target site, and also theprecise surface area to which energy should be delivered is oftenunknown and presently must be done by trial and error.

The present disclosure describes a system and method for determining theshape and location of the target site, which is called the reentryisthmus. U.S. Pat. No. 6,236,883 to Ciaccio et al describes a method tofind the isthmus based on signals acquired while the heart wasundergoing ventricular tachycardia.

Although this former method potentially represents a substantialimprovement over existing methods, it is not always convenient andcannot be used in all cases. For example during clinicalelectrophysiologic (EP) study, in which the clinician endeavors todetermine the target site to ablate the heart in the patient, it isattempted to initiate ventricular tachycardia by electrical stimulation.If tachycardia cannot be initiated, the former method described in theU.S. Pat. No. 6,236,883 to Ciaccio et al will not work because themethodology requires signals obtained from the heart surface duringventricular tachycardia. Furthermore, sometimes tachycardia can beinitiated but there is poor hemodynamic tolerance, which means that thepumping of blood is so poor during the tachycardia that the doctor mustterminate it so that the patient does not experience syncope. The methodof the present disclosure addresses both problems.

In one embodiment of the present disclosure, the reentry isthmus may belocalized and its shape may be estimated based on sinus-rhythm signalsfrom the heart surface. Sinus-rhythm is the normal rhythm of the heart.Therefore, based on this methodology there may no longer be a need toinduce ventricular tachycardia in the patient's heart during clinical EPstudy.

The method of the present disclosure provides the clinician with atarget area to ablate the heart to stop reentrant ventriculartachycardia from recurring. Accuracy is important so that only thoseportions of the heart at which ablation is needed are actually ablated.Ablating other areas can increase the chance of patient morbidity, bydamaging regions of the heart unnecessarily. Also, there is less chancethat the patient will be required to have a repeat visit, which willreduce cost of the total procedure and reduce discomfort to the patient.Rapidity is important to reduce the amount of fluoroscopy time andtherefore reduce the radiation exposure to the patient, as well as costdue to the reduction in time for the procedure, and patient discomfort.

The method of the present disclosure is also an advance over previousmethods because there may be no need to acquire many signals directlyfrom the heart surface which is difficult and time consuming, for theprocedure. Instead, only the electrocardiogram (ECG) signal may beneeded during tachycardia. This ECG signal may be obtained during the EPstudy, or even via a Holter Monitor when the patient is ambulatory andthe heart undergoes an episode of tachycardia. Therefore, the method ofthe present disclosure may greatly improve the accuracy of targeting thebest ablation site to stop reentrant ventricular tachycardia even whentachycardia cannot be induced or is hemodynamically stable, both ofwhich occur in a significant number of patients.

Treatment of reentrant ventricular tachycardia by catheter ablationmethods is hampered by the difficulty in localizing the circuit,particularly when the circuit structure is complex, the tachycardia isshort-lived, or when reentry is not inducible during electrophysiologicstudy [1]. If measurements of sinus rhythm activation could be used toaccurately localize reentry circuit features, it could potentiallygreatly improve the cure rate under these circumstances. A number ofclinical and experimental studies to determine the usefulness of sinusrhythm parameters for targeting reentry circuits have been reported. Thetime of latest depolarization during sinus rhythm has been partiallycorrelated to the location of the reentry isthmus; however, therelationship is inexact [2-3]. At the border zone, both normal andabnormal (low-amplitude, fractionated, or wide-deflection) electrogramsare present [2-5]; however, these abnormal electrograms can be presentboth within and away from the reentry circuit location and are thereforenot a specific predictor of its position in the border zone. Therefore,methods for detection and measurement of abnormal sinus rhythmactivation characteristics are not presently sufficient for targetingreentry circuits for catheter ablation, although presence of abnormalitysuggests the proximity of arrhythmogenic substrate.

When a reentrant circuit can be induced in the infarct border zone byprogrammed electrical stimulation in a canine model [6], the area wherethe isthmus forms has at least two conspicuous substrate properties: 1)it is the thinnest surviving cell layer of any area of the border zone[6-7], and 2) there is disarray of gap-junctional intercellularconnections which extends the full thickness from the infarct to thesurface of the heart [8]. Since these substrate properties persistregardless of rhythm type, they may affect electrical conduction at theisthmus area during sinus rhythm. The hypothesis that these phenomenacould be quantified and used to predict reentry inducibility, andisthmus location and shape, when it occurs, was tested in this study.

SUMMARY

This disclosure provides a method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising the steps of: a) receiving electrogram signals from the heartduring sinus rhythm via electrodes; b) creating a map based on thereceived electrogram signals; c) determining, based on the map, alocation of the reentrant circuit isthmus in the heart; and d)displaying the location of the reentrant circuit isthmus.

This disclosure provides a method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising the steps of: a) receiving electrogram signals from the heartduring sinus rhythm via electrodes; b) creating a map based on thereceived electrogram signals; c) finding a center reference activationlocation on the map; d) defining measurement vectors originating fromthe center reference activation location; e) selecting from themeasurement vectors a primary vector indicating a location of thereentrant circuit isthmus in the heart; and f) displaying the locationof the reentrant circuit isthmus.

This disclosure provides a system for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising: a) an interface for receiving electrogram signals from theheart during sinus rhythm via electrodes; b) processing means forcreating a map based on the received electrogram signals, anddetermining, based on the map, a location of the reentrant circuitisthmus in the heart; c) a display adapted to display the location ofthe reentrant circuit isthmus.

This disclosure provides a system for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising: a) receiving means for receiving electrogram signals fromthe heart during sinus rhythm via electrodes; b) storage means forstoring electrogram data corresponding to the electrogram signalsreceived by the receiving means; c) processing means for retrieving theelectrogram data, creating a map based on the electrogram signals,finding a center reference activation location on the map, definingmeasurement vectors originating from the center reference activationlocation, selecting from the measurement vectors a primary axis vectorindicating a location of the reentrant circuit isthmus in the heart,finding threshold points of the electrogram signals on the map, andconnecting the threshold points to form a polygon indicating a shape ofthe reentrant circuit isthmus in the heart; and d) a display fordisplaying one of the location and shape of the reentrant circuitisthmus.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1D are maps of a heart experiencing ventricular tachycardia inwhich long-runs of monomorphic reentry were inducible by center pacing.FIGS. 1A-1C are activation maps of the reentrant circuit. At the fourmargins of the map are indicated their respective locations on theheart: the left anterior descending coronary (LAD), the base, lateralleft ventricle (LAT), and apex. The small numbers in boxes areactivation times at each of the recording sites. Isochrones are labeledwith larger numbers in boxes. The shaded area represents the place wherethe double loop merges during reentry (called the central common pathwayor reentry isthmus). A table in FIG. 1A contains ray numbers as well asthe results of linear regression analysis along each ray. For each raynumbered 1-8, the columns of the table show the slope of the regressionline, termed the activation gradient (AG), and linear regressioncoefficient (r²) values, termed the activation uniformity (AU). Thickblack lines designate regions of conduction block. Arrows show thedirection of wavefront propagation. FIG. 1D shows an electrogramduration map for the sinus-rhythm cycle of FIG. 1A. The locations of thereentry arcs of block from the activation map of FIG. 1C are shownoverlapped as thick black lines. Between the arcs of block is the actuallocation of the reentry isthmus. The estimated isthmus location,determined by activation and electrogram duration analysis, is inscribedby the small circles on the map. The estimated area approximatelyoverlaps the shape of the actual reentry isthmus.

FIGS. 2A-2D are activation and electrogram duration maps for anexperiment in which short-runs of monomorphic reentry were inducible bypacing from the basal margin. This figure shows that as for cases inwhich long-runs (greater than 10 heartbeats) are recorded, even whenventricular tachycardia is of very short duration (less than 10heartbeats) it is possible to estimate the reentry isthmus locationusing sinus-rhythm activation and electrogram duration mapping. Theactual reentry isthmus location is the area between the solid lines ofduration map FIG. 2D for one of the cardiac cycles. For another of thecardiac-cycles, the shape changed slightly as shown by the dotted lines.The estimated reentry isthmus for this case of ventricular tachycardiais denoted by the area inscribed by the small circles, and mayapproximately overlap the actual reentry isthmus.

FIGS. 3A and 3B show a database, represented as a scatter plot, and oneand two-dimensional boundary lines for classification of the primaryvector parameters of activation gradient (AG) and activation uniformity(AU) according to one embodiment of the present disclosure. In bothFIGS. 3A and 3B, the dotted line shows the best boundary-line toclassify those cases in which reentry may occur versus those cases inwhich reentry may not occur based on the sinus-rhythm activationgradient parameter. The boundary line separates most of the cases inwhich long-runs of monomorphic reentry could be induced (solid circles)to the left side of the plot, and most of the cases in which reentry wasnot inducible (open circles) to the right side of the plot, in FIGS. 3Aand 3B. For cases in which only short-runs of reentry were inducible(triangles), many of the points resided to the left of the line, i.e. itwas correctly classified for these cases that reentrant ventriculartachycardia would occur. In FIG. 3A, the dashed line denotes the besttwo-dimensional boundary to separate cases in which reentrantventricular tachycardia would versus would not be inducible based on thesinus-rhythm activation gradient and uniformity. This two-dimensionalclassification boundary improved classification by correctly adding twomore open circles (no reentry occurred) to the right side of theboundary-line. In FIG. 3B, the same procedure is used, with the sameresult, except that the parameters were the mean electrogram durationand the activation gradient.

FIGS. 4A-4Y are estimated isthmus parameters—experiments with long-runsof reentry. The actual reentry isthmus is the area between the arcs ofblock denoted by thick curvy black lines. The estimated reentry isthmusderived from electrogram duration and activation analysis is denoted bythe cross-hatched area. The estimated and actual reentry isthmuses oftencoincide. The location and direction of the primary axis determined fromactivation mapping is denoted by the arrow in FIGS. 4A-4Y, and in mostcases it approximately aligns with the long-axis (i.e., entrance to exitdirection) of the reentry isthmus. The dashed line denotes the estimatedbest ablation line.

FIGS. 5A-5K are estimated isthmus parameters—experiments with short-runsof reentry. FIGS. 5A-5E are taken during polymorphic tachycardia wherethe electrocardiogram or ECG is irregular in period and/or shape of thesignal. FIGS. 5F-5K were taken during monomorphic tachycardia where theelectrocardiogram or ECG is regular in period and in shape of thesignal. FIGS. 5A-5K are the same as for FIGS. 4A-4Y except that thesecases included only short-runs, for example, less than 10 heartbeats ofventricular tachycardia. The method produces good overlap of estimatedwith actual reentry isthmus for most of the monomorphic cases; however,the overlap is less satisfactory for polymorphic cases because theseusually involve the occurrence of multiple reentry isthmusessimultaneously in the infarct border zone.

FIG. 6 is a regression line diagram according to one embodiment of thepresent disclosure.

FIG. 7 shows a flow chart of a method, according to an embodiment of thepresent disclosure, for identifying and localizing a reentrant circuitisthmus in a heart of a subject during sinus rhythm.

FIGS. 8A-8D show maps according to one embodiment of the presentdisclosure. In these figures the activation maps of the endocardialsurface during ventricular tachycardia are shown for four differentpatients. The thick black curvy lines denote arcs of conduction block,and the thinner curvy lines are isochrones of equal activation time,which are labeled. In FIG. 8A (patient 1), the wavefront proceedsbetween arcs of block at two areas. At the left of the map it crossesthe area between the arcs of block at a time of approximately 100milliseconds, and proceeds upward. At the right side of the map theactivation wavefront crosses the area between the arcs of block at atime of approximately 0 milliseconds and proceeds downward. Two distinctwavefronts from the left and right sides of the map coalesce at thecenter at time approximately 200 milliseconds. The process of thewavefronts looping around the arcs of conduction block rapidly and onceeach cardiac-cycle is known as reentry. The cycle-length of reentry forpatient 1 is approximately 333 milliseconds. (The last isochrone, 333milliseconds, is written as 0 milliseconds in the map.) In FIGS. 8B-8D(patients 6, 7, and 9) distinctive wavefronts similar course around arcsof conduction block once each cardiac-cycle.

FIGS. 9A-9D show maps according to one embodiment of the presentdisclosure. These are an example of how sinus-rhythm electrogramanalyses can be used to ascertain the position where the reentrantcircuit isthmus will form in the infarct border zone, and the best lineto ablate to stop ventricular tachycardia. FIG. 9A shows thesinus-rhythm activation map. The area of last activation is marked andproceeding from it are eight measurements vectors. The linear regressionresulting from each measurement vector is shown in the accompanyingtable. The vector with greatest activation uniformity and low activationgradient is ray 2 and it is in-spec. Hence ray 2 is the primary axis.The location of the primary axis is expected to coincide with thelocation of the reentrant circuit isthmus and the direction of theprimary axis denotes the predicted direction of the reentrant wavefrontas it passes through the isthmus during tachycardia. FIG. 9B shows theelectrogram duration map. Around the last-activating region ofsinus-rhythm and the primary axis so formed (not shown), points withdifferences in sinus-rhythm electrogram duration between recording sitesof, for example, >15 milliseconds, are denoted by circles. These circleson the computerized map grid are connected to for the polygonal surfacethat is the estimated location and shape of the reentrant circuitisthmus. The estimated best line to ablate, which bisects the estimatedisthmus into regions with equal surface area, is denoted by the dashedline and it is perpendicular to the primary axis (measurement vector 2in FIG. 9A). To the left of FIG. 9B, examples of electrograms in regionswith differing sinus-rhythm electrogram duration are shown. Whenelectrogram duration is long, the deflections occur for a longer timeduring each cardiac-cycle. FIG. 9C shows the activation map duringpacing. Note that the areas of last activation during pacing coincidewith region with long sinus-rhythm electrogram duration. This may be adirect result of the properties of the tissue (poorer conduction inregions of long sinus-rhythm electrogram duration when cycle-length isshorter as it is during pacing). FIG. 9D shows the activation map duringtachycardia. There is a reentrant circuit, and it occurs precisely aspredicted from the sinus-rhythm electrogram analyses. Ablating along theline denoted in FIG. 9B would cause reentrant ventricular tachycardia tocease because the electrical impulse would be blocked as it traversedthe actual isthmus area (FIG. 9D).

FIG. 10 shows estimated isthmuses according to one embodiment of thepresent disclosure. FIG. 10 shows the estimated isthmuses fromsinus-rhythm electrogram analyses (dashed lines) and best lines toablate (dotted lines), and the actual isthmuses determined fromactivation mapping during ventricular tachycardia (gray areas borderedby thick black curvy lines which denote locations of the actual arcs ofconduction block), for the 11 patients of the clinical study. The arrowsdenote the location and direction of the primary axis. In each case,there is agreement between the estimated and actual isthmus of thereentrant circuit. In many of the cases, ablating along the estimatedbest line, plus, for example, 10% more in each direction, would causethe electrical impulse to be blocked within the actual reentrant circuitisthmus; hence reentrant ventricular tachycardia would cease. In eachcase, the best estimated ablation line ablates little more of the heartthan is necessary, hence minimizing the chance of patient morbidity as aresult of the ablation procedure.

FIGS. 11A-11F show maps according to one embodiment of the presentdisclosure. These figures show an example of sinus-rhythm electrogramanalyses as well as PLATM.

FIG. 12 shows a table of Patient Clinical Data. The patient number, sex,infarct location, time from myocardial infarct to EP study, drugtherapy, and VT cycle length at onset are given.

FIG. 13 shows a diagram of a system according to an embodiment of thepresent disclosure.

FIG. 14A shows a flow chart of a method, according to an embodiment ofthe present disclosure, for identifying and localizing a reentrantcircuit isthmus in a heart of a subject during sinus rhythm.

FIG. 14B shows a flow chart of a method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,according to another embodiment of the present disclosure.

FIG. 15A shows a flow chart of a method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,according to another embodiment of the present disclosure.

FIG. 15B shows a flow chart of a method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,according to another embodiment of the present disclosure.

FIG. 16A shows a high-level block diagram of a system, according to anembodiment of the present disclosure, for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm.

FIG. 16B shows a high-level block diagram of a system for identifyingand localizing a reentrant circuit isthmus in a heart of a subjectduring sinus rhythm, according to another embodiment of the presentdisclosure.

FIGS. 17A-17D are maps used for skeletonization procedures. FIG. 17Ashows a reentry activation map. FIG. 17B shows a skeletonized reentrymap. FIG. 17C shows a sinus-rhythm pace map. FIG. 17D shows asinus-rhythm electrogram duration map. Locations of recording sites areshown by small numbers that indicate activation time (FIG. 17C), andanatomic landmarks are labeled (FIG. 17A).

FIGS. 18A-18T show summaries of skeletonized geometric variables for 20canine experiments (isthmus length, width, narrowest width, angle, andXY location in infarct border zone are shown in each figure). Narrowestwidth is *drawn at isthmus center for simplicity.

FIG. 19 shows mean skeletonized reentry circuit parameters frommeasurements of all experiments. LAT indicates lateral.

FIG. 20 shows a table of significant correlation relationships betweenskeletonized variables at the onset of stable tachycardia cycle length.

FIGS. 21A-21E show actual (black) versus estimated (gray) reentrycircuit arcs of block for 5 test-set experiments. Actual reentryactivation isochrones and tachycardia cycle length measured from R-Rinterval are also shown in each figure.

FIGS. 22A-22I show activation and electrogram duration maps for anexperiment in which long runs of monomorphic reentry were inducible bypremature stimulation from the base.

FIGS. 23A-23Y show comparisons of longest estimated (blue) versus actual(black) arcs of conduction block and breakthrough point locations forpremature excitation cycles leading to reentry in experiments withinducible tachycardia. Times in milliseconds at lower left of eachfigure give sinus rhythm cycle length (above) and S2 coupling interval(below). FIGS. 21A-21J correspond to 196 bipolar electrode recordingarray, and FIGS. 21K-21Y correspond to 312 bipolar electrode recordingarray.

FIGS. 24A-24C are scatter plots of electrogram parameters used forclustering and classification based upon whether or not reentrantventricular tachycardia would be expected to occur in the infarct borderzone. Lines show linear discriminate functions for best separation ofexperiments into those with versus without inducible reentry (solid andopen circles, respectively). Solid lines show best two-dimensionallinear discriminant function. Dashed lines show best one-dimensionallinear discriminate function. Only relationships with >80% accuracy areshown. FIG. 24A shows mean difference in activation time across thelongest estimated unidirectional arc versus its length. FIG. 24B showsmean difference in activation time versus mean electrogram duration inthe border zone. FIG. 24C shows difference in activation time atproximal versus distal edge of the breakthrough point versus time fromS2 stimulus to proximal edge of breakthrough point.

FIG. 25 shows quantitative parameters of premature excitation.

FIG. 26 shows significant regression relationships of prematureexcitation parameters.

FIGS. 27A-27F show activation and electrogram duration maps whichillustrate a method, according to one embodiment, for identifying andlocalizing a reentrant circuit isthmus in a heart of a subject duringsinus rhythm.

FIGS. 28A-28I show sinus rhythm electrogram duration maps for nineexperiments in which multiple reentrant circuit morphologies occurred.

FIGS. 29A-29I are maps which show locations of the actual arcs ofconduction block during reentry, versus the predicted location of eachreentrant circuit isthmus.

DETAILED DESCRIPTION

This disclosure provides methods for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm.The method, according to one embodiment (FIG. 14A), comprises the stepsof: a) receiving electrogram signals from the heart during sinus rhythmvia electrodes (step S141); b) creating a map based on the receivedelectrogram signals (step S142); c) determining, based on the map, alocation of the reentrant circuit isthmus in the heart (step S143); andd) displaying the location of the reentrant circuit isthmus (step S144).

In one embodiment of the above method, step b) includes arrangingactivation times of the received electrogram signals based on a positionof the respective electrodes.

In one embodiment of the above method, the activation times are measuredfrom a predetermined start time until reception of a predeterminedelectrogram signal.

In one embodiment of the above method, the map includes isochrones foridentifying electrogram signals having activation times within apredetermined range.

In one embodiment of the above method, step c) includes finding a centerreference activation location on the map by averaging an electrodecoordinate position of a predetermined number of electrogram signalsselected based on an activation time.

In one embodiment of the above method, step c) includes definingmeasurement vectors originating from the center reference activationlocation and extending outward on the map, the measurement vectors usedto designate the electrodes located along the measurement vectors.

In one embodiment of the above method, the electrodes assigned to ameasurement vector are chosen according to a distance from themeasurement vector. In one embodiment of the above method, theelectrodes assigned to a measurement vector are a subset of theelectrodes chosen according to a distance from the measurement vector.

In one embodiment of the above method, step c) includes selecting fromthe measurement vectors a primary axis vector having one of anactivation gradient value within a predetermined range and a highestactivation uniformity value within a predetermined range and where theprimary axis vector indicates a location of the reentrant circuitisthmus.

In another embodiment, step (c) includes selecting from the measurementvectors a primary axis vector having one of a mean electrogramactivation duration within a predetermined range, an activation gradientvalue within a predetermined range and a highest activation uniformityvalue within a predetermine range and where the primary axis vectorindicates the location of the reentrant circuit isthmus.

In one embodiment of the above method, the activation uniformity valueis a coefficient of linear regression. In one embodiment of the abovemethod, the activation uniformity value is a coefficient of non-linearregression. In one embodiment of the above method, the activationuniformity value is a variance in activation times along a selectedmeasurement vector. In one embodiment of the above method, theactivation uniformity value is a measure of variability along a selectedmeasurement vector.

In one embodiment of the above method, the activation gradient value isa slope of a linear regression line.

In one embodiment of the above method, the activation gradient value isa slope of a non-linear regression line. In one embodiment of the abovemethod, the activation gradient value is a mean absolute difference inactivation times along a selected measurement vector. In one embodimentof the above method, the activation gradient value is a difference alongthe measurement vector.

In one embodiment of the above method, step c) includes, when a primaryaxis vector is not found, finding an alternate center referenceactivation location on the map by averaging an electrode coordinateposition of a predetermined number of electrogram signals having analternate characteristic, defining measurement vectors originating fromthe alternate center reference activation location and extending outwardon the map, the measurement vectors used to designate the electrodeslocated along the vectors, and selecting from the measurement vectors aprimary axis vector having one of an activation gradient value within apredetermined range and a highest activation uniformity value within apredetermined range.

In one embodiment of the above method, step d) includes when a primaryaxis vector is not found, selecting from the measurement vectors aprimary axis vector having one of an activation uniformity value withina predetermined range and a highest gradient value within apredetermined range.

According to another embodiment of the above method (FIG. 14B), theabove method further comprises the steps of: e) determining, based onthe map, a shape of the reentrant circuit isthmus in the heart (stepS145); and f) displaying the shape of the reentrant circuit isthmus(step S146).

In one embodiment of the above method, step b) includes generatingduration values representing a time difference between a starting pointand a stopping point in the electrogram signals.

In one embodiment of the above method, the one of the starting point andstopping point is computed to be when an amplitude of the electrogramsignal is within a predetermined amount of an amplitude of theelectrogram signal.

In one embodiment of the above method, step e) includes findingthreshold points in which the difference in electrogram duration valuesbetween adjacent sites is greater than a predetermined time interval.

In one embodiment of the above method, step e) includes connecting thethreshold points to form a polygon encompassing the center referenceactivation location.

In one embodiment of the above method, step e) includes connecting thethreshold points to form a polygon encompassing the center referenceactivation location and a predetermined portion of the primary axisvector and indicating a shape of the reentrant circuit isthmus in theheart.

According to another embodiment of the above method, the above methodfurther comprises the steps of: g) determining an ablation line toablate the heart based on the location of the reentrant circuit isthmus(step S147); and h) displaying the ablation line (step S148).

In one embodiment of the above method, step g) includes drawing theablation line on the map bisecting the polygon and at a predeterminedangle with respect to the primary axis vector.

In one embodiment of the above method, the ablation line traverses thepolygon plus a predetermined distance.

This disclosure provides another method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm(FIG. 15A), comprising the steps of: a) receiving electrogram signalsfrom the heart during sinus rhythm via electrodes (step S151); b)creating a map based on the received electrogram signals (step S152); c)finding a center reference activation location on the map (step S153);d) defining measurement vectors originating from the center referenceactivation location (step S154); e) selecting from the measurementvectors a primary vector indicating a location of the reentrant circuitisthmus in the heart (step S155); and f) displaying the location of thereentrant circuit isthmus (step S156).

In one embodiment of the above method (FIG. 15B), the above methodfurther comprises the steps of: g)finding threshold points of theelectrogram signals on the map (step S157); h) connecting the thresholdpoints to form a polygon indicating a shape of the reentrant circuitisthmus in the heart (step S158); and i) displaying the shape of thereentrant circuit isthmus (step S159).

In one embodiment of the above method, the above method furthercomprises the steps of: j) finding an ablation line based on the polygon(step S160); and k) displaying the ablation line (step S161).

According to one embodiment, the primary axis vector may have a meanactivation duration in a predetermined range.

A method for identifying and localizing a reentrant circuit isthmus in aheart of a subject during sinus rhythm, according to one embodiment,comprises determining a late-activation location during sinus rhythm,then determining the areas of short electrogram duration which areconnected to this region, and determining the curved vector along eachtract of short electrogram duration which has a uniform and slow sinusrhythm activation gradient.

FIGS. 27A-27F illustrate the method. The sinus rhythm activation timemap is shown in FIG. 27A and the sinus rhythm activation duration map,measured from the same cardiac cycle at the beginning of a selectedexperiment, is shown in FIG. 27B. Isochrones of like activation time aredrawn on the activation time map at 10 ms intervals (FIG. 27A). Threeshort arcs of conduction block, denoted by thick curved black lines,occurred during sinus rhythm. There is an area of late activation whichcenters on the 50 ms isochronal interval adjacent to the arc ofconduction block closest to the LAD margin (FIG. 27A). At this location,activation duration is short and using an activation duration of 30 msas a threshold, extends in three tracts away from the center point (FIG.27B). The locations of these tracts of short sinus rhythm activationduration are superimposed on the activation times map as a shaded region(FIG. 27A). Along each tract, curved vectors are drawn where the sinusrhythm activation time gradient was most uniform and steep with theminimum thresholds as given above (colored red, blue, and green). Basedon this vector determination of the extent of uniform slow conductionalong each tract, the positions where arcs of conduction block would beexpected to occur during reentrant tachycardia are drawn at the edges ofthe tracts along the extent of the vectors. For this experiment, itwould be expected that three reentrant ventricular tachycardiamorphologies would occur, with the locations of the isthmus of thereentrant circuits given by the solid lines colored red, blue, andgreen.

In FIG. 27C, premature stimulation from the basal margin of the gridthat led to reentrant tachycardia is shown. During the prematureexcitation cycle, several long arcs of block formed, which mostlycoincide with regions where the sinus rhythm activation time gradient issharp (FIG. 27A) and where there are sharp transitions in sinus rhythmactivation duration (FIG. 27B). Upon premature stimulation (FIG. 27C)the wave-front first proceeds along a tract of short activation durationas denoted by the gray shaded area (isochrones 20-80 ms near the basalmargin), and along the LAD margin. After arcing along the large blockline, the distinct wave-fronts coalesce near the apical margin and thenpropagate as a coherent wavefront along another of the tracts of shortelectrogram duration. Breakthrough occurs where activation duration isvery short and the location is denoted by the blue arrow. This prematureexcitation cycle was followed by reentrant tachycardia of themorphologic type shown in FIG. 27D. In FIG. 27D, the estimated arcs ofblock for this morphology are denoted by thick blue lines, and theyfollow the tract of short sinus rhythm activation duration that leadstoward the LAD-basal margin of the mapping grid. They estimated arcs ofconduction block approximately coincide with the actual arcs ofconduction block (thick curved black lines) and the direction ofpropagation during the diastolic interval of reentry is the same forboth the estimated and the actual isthmus characteristics. Thewave-front coalesces and enters the isthmus in coincidence with anotherof the tracts of short sinus rhythm activation duration and with thecenter point location. In FIGS. 27D and 27E the other two reentrantcircuit morphologies that were inducible in the infarct border zone byprogrammed electrical stimulation in this experiment are shown. Theestimated arcs of conduction block (green and red) closely correspondwith the actual arcs of conduction block during reentry (black). Theactual isthmus location resides along a tract of short sinus rhythmactivation duration, and the wave-front tends to propagate along tractsof short activation duration for some distance preceding the entrance tothe isthmuses and following exit from the isthmus locations.

FIGS. 28A-28I show the sinus rhythm electrogram duration maps for nineexperiments in which multiple reentrant circuit morphologies occurred.Shown are the vectors of uniform, shape sinus rhythm activationgradient, and the locations of the estimated arcs of conduction blockduring reentry at the edges of the tracts of short activation duration.FIG. 28C depicts the experiment of FIGS. 27A-27F in which threereentrant circuit morphologies occurred. The configuration for theexperiment of FIG. 28D suggests that a third morphology might have beeninducible with the exit pointing toward the apical margin. However, novector with uniform, steep sinus rhythm activation gradient within theminimum thresholds as described in the Methods could be drawn along thattract of short activation duration. In FIGS. 28B, 28E, and 28F, areaswith longer activation interrupted the tracts near their centers (whitepatches within the gray shaded regions). Portions of the edges of theseareas were predicted to form arcs of conduction block during reentrywhere they were adjacent to a vector of uniform steep gradient. In FIGS.28G and 28H, the tracts of short activation duration abutted each otherto form a single, more or less linear tract. In these experiments,breakthrough at the end of the premature excitation cycle occurred alongan edge of the tract and turned one way or another depending on thepropagation direction and timing with respect to the previously excitedregion.

FIGS. 29A-29I show the locations of the actual arcs of conduction blockduring reentry, versus the predicted location of each reentrant circuitisthmus. The estimate in red corresponds to the actual arcs of blockshown in black. The estimate in blue corresponds to the actual arcs ofblock shown in medium gray. The estimate in green (FIG. 29C only)corresponds to the actual arcs of block shown in light gray. Whereestimated isthmus morphologies depicted in blue and red overlap, thearea is denoted by violet color (FIGS. 29A, 29C, 29D, 29F, 29H and 29I).Where green and red overlap, the area is denoted by brown color (FIG.29C). Where three isthmus locations overlap, the area is denoted byolive drab color (FIG. 29C). The small arrows denote the actualdirection of wavefront propagation within the isthmus during reentry,which was always in the direction predicted, away from thelate-activating region of sinus rhythm along each tract of short sinusrhythm activation duration. In most cases there is close correspondencebetween estimated and actual characteristics of the isthmuses of thereentrant circuit during each reentry morphology. In FIG. 29G, onemorphology was not as accurately predicted; however in this experimentthe infarct border zone possessed very poorly conducting areas evenduring sinus rhythm at the locations where the peripheral reentry arcsof block formed colored in gray. For all experiments, the mean overlapbetween estimated and actual reentry isthmuses was 84%. A single linedrawn at the point of abutment of the morphologies occurring during agiven experiment is shown by dashed light blue line. In most every case,an ablation lesion coinciding with the position of this line would beexpected to prevent all reentry morphologies from recurring, becausesuch a lesion would mostly or completely span the widths of all of theisthmuses for each reentry morphology. For the experiments of FIGS. 29Eand 29G, reentry isthmuses whose arcs of block are denoted in gray wouldnot be entirely spanned, but it is still possible that recurrence ofreentry would be prevented. Only for the experiment of FIG. 29H,morphology depicted in black, would the lesion location appear todefinitely fail to prevent recurrence of one of the episodes ofreentrant tachycardia. However, hypothetically, if a lesion were thenplaced across the estimated isthmus location, shown in red, at itscenter, it would span the actual isthmus width and prevent recurrence ofreentry (FIG. 29H).

This disclosure also provides a system for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm.The system, according to one embodiment (FIG. 16A), comprises: aninterface 165 for receiving electrogram signals from the heart duringsinus rhythm via electrodes; processing means 166 for creating a mapbased on the received electrogram signals, and determining, based on themap, a location of the reentrant circuit isthmus in the heart; and adisplay 167 adapted to display the location of the reentrant circuitisthmus.

According to another embodiment (FIG. 16B), the system comprises:receiving means 171 for receiving electrogram signals from the heartduring sinus rhythm via electrodes; processing means 173 for creating amap based on the electrogram signals, finding a center referenceactivation location on the map, defining measurement vectors originatingfrom the center reference activation location, selecting from themeasurement vectors a primary axis vector indicating a location of thereentrant circuit isthmus in the heart, finding threshold points of theelectrogram signals on the map, and connecting the threshold points toform a polygon indicating a shape of the reentrant circuit isthmus inthe heart; and a display 174 for displaying one of the location andshape of the reentrant circuit isthmus. The system may optionallyinclude storage means 172 for storing electrogram data corresponding tothe electrogram signals received by the receiving means, and theprocessing means 173 retrieves and processes the electrogram data fromthe storage means 172.

The interface, receiving means, processing means display and storagemeans are, respectively, described in more detail below.

The method of the present disclosure is used to target ablation sites onthe surface of the heart to stop reentrant ventricular tachycardia fromoccurring. It may be used to target sites on either the endocardial orthe epicardial surface of the heart. One embodiment of the presentdisclosure involves using signals acquired during sinus-rhythm, wheresinus rhythm is the normal rhythm of the heart these signals may beacquired during clinical electrophysiologic EP study with specialequipment designed for this purpose. Several types of catheters areavailable for this purpose when the reentrant ventricular tachycardia isbelieved to be endocardial in origin. When reentrant ventriculartachycardia is believed to be epicardial in origin, open chest surgeryor other procedures may be required to obtain signals and map conductionon the surface. The type of catheter may influence the data acquisitionmethod.

For example, in a noncontact clinical system, the probe does not contactthe heart surface, signals may be acquired and by a mathematical inverseequation, the signals that would occur on the heart surface may bereconstructed. When a standard clinical catheter is used, the cathetermay acquire signals from, for example, two adjacent locations at once,because there are two recording electrodes on the catheter, and thoseelectrodes are located close together. Data may be recorded over oneheartbeat during sinus-rhythm, and/or one heartbeat during ventriculartachycardia (and its cycle-length). Once the data signals are obtained,they are then analyzed according to the procedures described further inthe present disclosure.

The present disclosure can be incorporated into existing clinicalmethodology for catheter ablation for example, as computer software, oras a standalone computerized data acquisition and analysis system thatmay be implemented, for example, in software residing on a digitalcomputer, or in hardware components, for example, a specially designedintegrated circuit or circuits for maximum speed of processing. Thetarget ablation area, with relevant quantitative values, may be outputto a display, for example, a CRT monitor, so that the clinician mayrapidly make use of the information and guide the catheter or otherablation device. Alternatively, the target ablation area and otherrelevant values may be output in printed or other auditory, visual ortactile form.

FIG. 13 shows a high-level diagram of a system which may be adapted foridentifying and localizing a reentrant circuit isthmus in a heart of asubject during sinus rhythm according to one embodiment of the presentdisclosure. System 70 may include a processor 71, memory 72, hard disk73, removable storage 74, a display device 76 (for example, a CRT or LCDmonitor, which may have a touch screen display for input, a speaker, anda projection display), and other input/output devices 77. Such acomputer system 70 may be a personal or workstation computer, laptop orother portable computing device (for example, PDA) or may be astandalone system.

The computer system 70 may also include a network interface 78, forexample, a wired or wireless Ethernet card, for connecting to a network(for example, the Internet, an intranet, an extranet, a LAN (local areanetwork), a WAN (wide area network), a wireless network, a satellitenetwork and other networks) for communication with other electronicequipment. The network interface 78 includes the appropriateconventional units for interfacing with the networks, including, forexample, Ethernet card, modem, wireless modem, etc. Interfaces for suchcommunication are well known. Therefore, the interfaces are notdescribed in detail here.

The processor 71 also may be a suitably programmed microprocessor ormicrocontroller, an application specific integrated circuit (ASIC), aprogrammable logic device, or (as one skilled in the art shouldunderstand and appreciate) a collection of discrete components suitablylaid out and connected on a printed circuit board.

A computer program embodying the subject matter of this disclosure mayreside on or in, for example, the memory 72, hard disk 73 and/orremovable storage medium 74. Also, the computer program may bedownloaded to the device or system through network 78. The memory 72,hard disk 73 and removable storage 74 also may be used to store, forexample, system code, heart signal input data, user input parameters,and patient database values. The software components also may includehardware management functions, such as assorted device drivers,including a wireless communication driver if a wireless interface isprovided.

The program and data storage devices may include one or a combination ofbuffers, registers and memories [for example, read-only memory (ROM),programmable ROM (PROM), erasable PROM (EPROM), electrically erasablePROM (EEPROM), non-volatile random access memory (NOVRAM), etc.]. Otherstorage devices may include, for example, floppy disk drive, CD (or DVD)drive, hard disk, and other mass storage devices. The storage devicesmay include a storage area network (SAN).

The software components also may include a user interface. The userinterface provides means (in the form of well-known graphical interfaceelements, such as tables, menus, buttons, drop-down lists, tabs, etc.)for managing and configuring a library of patient data, including heartsignal input data, maps, etc. Further, a user, through the userinterface, can customize the images to be displayed.

As another example, a voice interface may be provided along with amicrophone. Spoken words are picked up through the microphone andconverted by applying speech recognition (software and/or hardware)technology. For example, a user, with visual prompt provided on thedisplay, such as in the form of text and/or graphics, may give an oralcommand, which is then converted through speech recognition and triggersoperation.

The input/output devices 77 may include, for example a keyboard, mouse,light pen, tactile control equipment, microphone, printer, scanner, aswell as one or more interfaces to electrodes, catheter and otherdevices. Such interfaces may include conventional data acquisition means(for example, one or more analog-to-digital (A/D) converters) or controlmeans (for example, a suitably programmed microcontroller). Thus, thesystem includes one or more interfaces for receiving electrogram signalsfrom the heart during sinus rhythm via electrodes.

In one embodiment of the present disclosure, the output may include aseries of maps that show, the sinus-rhythm activation characteristics inthe infarct border zone, the sinus-rhythm electrogram durationcharacteristics in the infarct border zone, the location of theestimated reentry isthmus in the infarct border zone, and the locationof the estimated best ablation line in the infarct border zone.

These maps may include numerical coordinates used to guide the clinicianas to the correct placement of the catheter to ablate the heart.

Other information may be output, including, for example, activation mapsof reentrant ventricular tachycardia, for example, if such is available,to confirm the computer selection of the target ablation area andprovide additional information to the clinician in order to modify thesuggested ablation site if necessary.

The measurement vectors in the XY space of the activation map are usedto define which sites are included in the analysis of activation times.The regression line is a line having as one dimension, the distancealong that measurement vector for which the particular regression wascalculated, and as the other, the values of the activation times alongthe measurement vector at each site.

FIGS. 3A-3B show database entries depicted as a scatter plot, and oneand two-dimensional boundary lines (dotted and dashed respectively) forclassification of the primary vector parameters of activation gradient(AG) and activation uniformity (AU) so that it may be predicted whetherthe patient ventricular tachycardia is due to a reentrant circuit at therecording surface. Either line is used separately for classificationpurposes. In FIGS. 3A-3B, the solid circles denote experiments in whichmonomorphic reentrant ventricular tachycardia occurred. The open circlesdenote experiments in which reentrant ventricular tachycardia did notoccur. The triangles denote experiments in which reentrant ventriculartachycardia occurred but is was due to a polymorphic tachycardia. Thelatter may be the most difficult to classify.

FIG. 3A shows the relationship between AG and AU for data obtained inapproximately 50 canine experiments. Although the canine heart model isnot precisely the same as reentrant ventricular tachycardia in humans,there is a close correspondence and hence the scatter plot data servesas a model or guide for human patients. Each point represents the AU andAG of a primary vector from each canine experiment in thetwo-dimensional (XY) space. The lines drawn in the scatter plot denotethe best one-dimensional (vertical line) and two-dimensional (horizontalline) boundaries for classifying those canine hearts in which it ispredicted that reentrant ventricular tachycardia will occur at therecording surface versus those in which it is predicted not to occur.For the canine experiments whose AG/AU point is plotted to the left ofthe lines, reentry is predicted to occur.

For the canine experiments whose AG/AU point is plotted to the right ofthe lines, reentry is predicted not to occur at the recording surface.In such cases where reentrant ventricular tachycardia is predicted notto occur at the recording surface, it may still occur at the oppositesurface of the heart or in the interior of the heart. For example,recordings were made in the canine heart along the epicardial surface.Reentry may occur at the endocardial surface in these cases. Ventriculartachycardia in some of these experiments may be caused by a focal pointrather than a reentry loop. Such information is highly important to theclinician during ablation therapy.

In FIG. 3B, the parameters used are the activation gradient and theelectrogram duration. Similar results as those of FIG. 3A are obtained.The parameters can be used to predict whether or not reentrantventricular tachycardia will occur with the same accuracy as in FIG. 3A.In FIGS. 3A and 3B, the activation gradient (AG) alone is a goodclassifier of whether or not reentrant ventricular tachycardia willoccur, as can be seen by the vertical line (one-dimensional boundary) ineach figure. In contrast, the activation uniformity (AU) of FIG. 3A andthe electrogram duration of FIG. 3B alone would not be good classifiers,for example, a one-dimensional boundary or line in the horizontaldirection, may not provide a good classifier either in FIG. 3A or inFIG. 3B.

FIG. 6 shows a sample regression line diagram according to oneembodiment of the present disclosure. The axes are the distance alongthe measurement vector (X-axis) and the activation time at the recordingsite located at each distance (Y-axis). There are 5 points which is thenumber of values used for the experimental study of Ciaccio et al, Jul.31, 2001, and for the clinical study of Ciaccio et al submitted. Forregression analysis, a minimum number of points, for example, 5, may beused. The line in the graph is the regression line, which is the line atwhich the mean distance to the points is minimized based on theleast-squares error criterion. The closer the fit of the points to theline, the higher the coefficient of linear regression (r² value orlinearity) and therefore the higher the activation uniformity. Thehighest uniformity is when all of the points reside on the line (perfectlinearity or r²=1.0). The poorer the fit of the points to the line, thelower the coefficient of linear regression and therefore the lower theactivation uniformity. The lowest uniformity is when all of the pointsare randomly scattered (no linearity or r²=0.0).

FIG. 7 provides a flow chart diagram of one embodiment of the methodaccording to the present disclosure. In Step S100, a catheter may bepositioned within the left ventricular chamber of the heart duringsinus-rhythm, and electric measurement signals may be recorded fromthroughout the surface of the heart at different recording sites duringsinus-rhythm using a catheter attached to a data acquisition device. Asdescribed above, if a noncontact probe or electrode array is used, forexample, a basket catheter, these recording measurements may be madesimultaneously. If a standard ablation catheter with two electrodes isused, the recoding measurements may be made in turns.

Once the measurement signals are received, an activation map (FIG. 1A)and an electrogram duration map (FIG. 1D) may be constructed based onthe recorded signals in Step S102. In this step, the measurements may bemapped from the recording sites onto their respective portions of theheart.

In Step S104, based on the activation map, the last-activating region XYcenter, shown by the cross-hair in FIGS. 1A, 1D, 2A, and 2D, may bedetermined by comparing the activation times of the recorded sites, andthe method may select a number of sites in a region having latestactivation times. The latest activation region may include, for example,a contiguous region of five or more sites.

To determine which recording sites may be used for analysis, first theXY center of last activation is determined. Then the measurement vectorsmay be positioned with the hub at the XY center. Along these measurementvectors may be marks, for example, at some equal spacing 1 centimeterapart. For each mark, the recording site which is closest to it in theXY directions may be chosen as the site whose activation time is used asthe measurement value for that point. This may be done for marks alongeach measurement vector, for example, for 5 marks. When the activationtimes to be used for analysis have been determined, the linearregression of these times may be computed according as shown, forexample, in FIG. 6, which shows a plot of the linear regression line.

The last-activating region XY center is determined and, in Step S106,vectors may be chosen with origins at the last-activating region XYcenter. In one embodiment of the present disclosure, vectors may bechosen, for example, as 8 vectors separated by a difference inorientation of 45 degrees with one vector oriented directly vertical inthe map. Activation times may then be determined along the vectorsoriginating from the XY center.

In Step S108, linear regression is computed for the times along eachvector. Linear regression assumes an association between the independentand dependent variable that, when graphed on a Cartesian coordinatesystem, produces a straight line. Linear regression finds the straightline that most closely describes, or predicts, the value of thedependent variable, given the observed value of the independentvariable. The equation used for a Simple Linear Regression is theequation for a straight line, where y is the dependent variable, x isthe independent variable, b0 is the intercept, or constant term (valueof the dependent variable when x=0, the point where the regression lineintersects the y axis), and b1 is the slope, or regression coefficient(increase in the value of y per unit increase in x). As the values for xincrease, the corresponding value for y either increases or decreases byb1, depending on the sign of b1.

Linear Regression is a parametric test, that is, for a given independentvariable value, the possible values for the dependent variable areassumed to be normally distributed with constant variance around theregression line. Linear regression routines work by finding the best fitstraight line through the data points. By “best fit” it is meant thatthe line is optimally positioned, based an error criterion, so that themean distance to all the points on the graph is minimized. The errorcriterion used is called the least squares error, or sum of thedistances from each point to the point on the line that forms aperpendicular angle.

In step S110, the activation gradient (AG) and uniformity (AU) whichare, respectively, the slope of the regression line and the coefficientof linear regression, are determined from the activation times alongeach vector. The slope of the linear regression line is the value b₁ inthe equation for a straight line: y=b₁x+b₀.

In step S112, the method of the present disclosure searches for aprimary axis vector. The primary axis vector is the vector withactivation gradient and uniformity within a specified range, forexample, the vector with steepest gradient and greatest uniformity ifmore than one vector have parameters in range. The steepest gradient isthat in which there is the largest change in activation time per unitdistance along the vector, for example, Δt/Δx is maximized, where t isthe activation time and x is the distance along the measurement vector.When the slopes are negative, this means the largest negative gradient,because larger negative numbers are steeper, and smaller negativenumbers, those closer to zero, are shallower. The conduction velocity isthe inverse of the activation gradient, for example, Δx/Δt and thereforeconduction velocity is diminished as the activation gradient increases.

Areas along which the isthmus forms may have diminished sinus-rhythmconduction velocities. The method of the present disclosure may scaleΔt/Δx by a factor of, for example, ⅕ or 0.2, which may represent thedistance between recording sites of approximately 5 centimeters.Conduction velocities below, for example, 0.75 meters per second(millimeters per millisecond), may be generally found along the primaryaxis, which may be converted to activation gradient, 1/(0.75)=4/3=1.33.The scale may be reversed, for example, 1.33/0.2∓6.5, which is the slopeof the regression line for a conduction velocity of, for example, 0.75m/s. Hence, a regression line slope of, for example, −6.5 or steeper(greater negative value) may indicate the conduction velocity is at orbelow, for example, 0.75 m/s. When conduction velocity falls belowabout, for example, 0.25 m/s, the area may not be one in which thereentrant circuit isthmus will form. Hence, there may be a range ofsinus-rhythm gradients in which reentrant ventricular tachycardia wouldbe expected to occur.

Uniformity is the proximity of the coefficient of linear regression to1.0. At 1.0, all of the points in the regression plot are on theregression line and there is perfect uniformity of conduction all alongthe location of the measurement vector. The minimum value that thecoefficient of linear regression may have is 0.0 which means that thepoints in the regression line scatter plot are completely random; thereis no uniformity. Higher uniformity means that the individual or localconduction velocities, i.e., the distance between any two sites dividedby the distance in activation times between those same sites, becomemore and more similar from site-to-site among the sites used foranalysis along a measurement vector.

If no vector has parameters within range, then no primary axis vector isselected at this time. (No, Step S112) In Step S114, the method of thepresent disclosure then may search for an XY center of another regionwith contiguous, late-activation times. If there is an XY center oflate-activating region of sinus-rhythm with parameters within range,(Yes, Step S114) then the method returns to Step S106, where vectors arechosen based on the new XY center and the method continues.

The process for searching for any XY center of late-activation may beperformed as follows. Determine late sites at which adjacent orneighboring sites activate earlier in time. A late site is a site whoseactivation time follows that of all neighboring sites. These neighboringsites can be those, for example, closest to it in the vertical,horizontal, and diagonal directions. From the time of a given late site,include in the late-activation area of that late-site those contiguoussites with activation preceding the late site by a predetermined numberof milliseconds, for example, 10 milliseconds. If the late site plus therecording sites contiguous with it are greater than some number forexample, 5 sites in total, then count the area so formed as one oflate-activation. Compute the XY-center as the mean distance in the X andin the Y directions on the computerized map grid for all of thecontiguous sites in the late-activation area. Repeat this procedure forall late sites. Of the resulting late-activation regions, determinewhether or not a primary axis in-spec, that is, with activation gradientand activation uniformity along the primary axis meeting the morestringent threshold criteria of S112, is present first at thelast-activation regions whose late site activates last among all of thelate sites. If no measurement vector meets the more stringent thresholdcriteria of S112, continue this procedure for the last-activation regionwhose late site activates next-to-last among all of the late sites.

If there is not another XY-center of late activation (No, Step S114),then in Step S116, the vector with steepest gradient within apre-specified range that is also within a pre-specified range ofuniformity may be chosen as the primary axis and the method continues toStep S120.

The more stringent ranges specified in the initial search for a primaryaxis vector in Step S112 may not be the same as those ranges specifiedin the subsequent search for a primary axis vector in Step S116. Theless stringent ranges used in Step S116 will be a different standardthan in Step S112. The standard for S112 may be uniformity r² between,for example, 0.8 and 1.0, and gradient below, for example, −6.5 to −20slope of the regression line with conduction velocity between, forexample, 0.75 m/s and 0.25 m/s. The standard for S116 may be uniformityr² between, for example, 0.6 and 1.0, and gradient below, for example,−3.3 to −20 slope of the regression line with conduction velocitybetween, for example, 1.5 m/s and 0.25 m/s.

If the primary axis vector is within the range of activation gradientand uniformity (Yes, Step S112), then ventricular tachycardia due to areentrant circuit may be predicted to occur. The primary axis vector isa line that may indicate the approximate location of the reentryisthmus, in the sense that the primary vector overlaps a part of theactual reentry isthmus, and the orientation of the primary vector may beapproximately in-line with the actual reentrant circuit isthmus. Theprimary axis vector may point in the direction from the location wherethe activating wavefront enters the isthmus to the place where it exitsthe isthmus.

If the primary axis is not within range (No, Step 112), then ventriculartachycardia due to a reentrant circuit may not be expected to occur. Ifreentrant ventricular tachycardia is not predicted to occur, then theclinician may be informed through the computer hardware/software thatthe ventricular tachycardia episodes are not due to a reentrant circuit.The clinician may then modify the diagnostic procedure accordingly.

In another embodiment of the present disclosure, a scatter plot may beused to predict whether ventricular tachycardia will occur at therecording surface for the patient. The scatter-plot is a graphicalrepresentation of a data base consisting of the data from previouspatients or experimental results which are used as exemplars. The one-and two-dimensional boundary lines are used to classify any new patient(input) for the parameters measured along the primary axis of activationgradient versus activation uniformity (FIG. 3A), or activation gradientversus electrogram duration (FIG. 3B). If the point from the new inputresides to the left of the one or the two dimensional line, it ispredicted that reentrant ventricular tachycardia will occur at therecording surface for the patient; otherwise not. Either FIG. 3A or FIG.3B may be used for this classification.

If there is no reentry predicted, but there is ventricular tachycardia,one of two possible events may be occurring: ventricular tachycardia isfocal (ectopic). These tachycardias may be cured if they can be induced.In this case, from the ventricular tachycardia activation map, the pointof first activation is the focus, and the clinician may ablate thispoint to stop tachycardia (there is no circuit or loop, just a point orfocus). In another event, there is reentry, but it is occurringelsewhere in the heart other than the surface (endocardial orepicardial) where recordings are being made. For example, if recordingsare made from the endocardium with the catheter, the reentry circuit maybe located in the epicardium. If the clinician knows the location of theepicardial circuit, it may be possible to ablate through the heart wallfrom endocardium to epicardium, using a higher radiofrequency energy, tostop tachycardia. This entails more damage to the heart and thereforemore chance of morbidity to the patient.

If a primary axis vector is found (Yes, Step S112) then reentry may bepredicted to occur, and in Step S118, the location of the primary axisvector may be plotted on the computerized electrogram duration map.

In Step S120, points are determined where the difference in electrogramduration between adjacent sites may be greater than some threshold, forexample, 10-15 milliseconds.

In Step S122, those points may be connected to form a polygonal surfaceencompassing the XY center of the last-activating region so as tominimize the maximum distance between any two connected points, andminimize the average distance between connected points. The surface areaof the polygon may be above a pre-defined threshold, for example, 4centimeters square. The polygonal surface may encompass, for example, atleast the first 1 cm in length of the primary axis that originates fromthe XY center of the last-activation region. The polygonal surface soformed may be an estimate of the location and shape of the centralcommon pathway (isthmus) of the reentrant circuit.

To connect the points to form the polygonal surface, points on thecomputerized sinus-rhythm electrogram duration map grid in which thedifference in electrogram duration between adjacent sites is greaterthan, for example, 15 milliseconds, may be marked. The points may beconnected to encompass the XY center of late-activation determined fromthe sinus-rhythm activation map, and also so as to encompass the first,for example, 1 centimeter, of the location of the primary axis from itsorigin at the XY center of late-activation.

The points that are connected may be adjusted so as to minimize themaximum difference between points. The points that are connected may beadjusted so as to minimize the mean difference between points. Theminimum surface area of the polygon formed by connecting the points maybe greater than, for example, 4 centimeters squared (cm²). The polygonso formed may be an estimate of the location and shape of the isthmus ofthe reentrant circuit that forms during ventricular tachycardia.

In step S124, the estimated ablation line is determined so as to bisectthe estimated central common pathway into halves with equal surfaceareas, or with unequal areas, for example, 25% and 75%. The direction ofthe ablation line may be perpendicular to the primary axis, where theprimary axis approximates the direction of the long-axis of the centralcommon pathway. The length of the estimated ablation line may extendacross the estimated central common pathway and may extend further, forexample, 10%, to ensure the central common pathway is ablated across itsentirety.

In another embodiment, the method of the present disclosure maydetermine whether ventricular tachycardia is due to reentry by plottingthe activation gradient and uniformity of the primary axis in a scatterplot with points, for example, from other tachycardias from otherpatients that were used for learning (exemplars), as shown, for examplein FIGS. 3A and 3B. Based on the location of the new point on eitherside of the linear or nonlinear classification boundary, whether or notreentry will occur may be predicted. For example, if the data point ofthe patient lies to the left of the two-dimensional classificationboundary line, reentry may be predicted to occur, else not. In FIG. 3A,two 1-dimensional thresholds were used, and in FIG. 3B, a single2-dimensional threshold was used for classification.

In the case where no measurement vector meets the most stringentcriteria at any late-activating region (No, Step S112), then the reducedstringency criteria may be emplaced in which the best of any of themeasurement vectors originating from any of the late-activating centerspresent may be made the primary vector. In this case, reentry may bepredicted not to occur. The AG and AU for this primary vector may beused as a new point in the database for the scatter plot. It may alsopoint to whether the tachycardia may be due to a focus (point source) orwhether it may be reentry but located on the other surface of the heart(epicardium versus endocardium).

FIG. 11 shows another example of how electrogram analyses may be used todetermine areas of the reentrant ventricular tachycardia circuit. InFIG. 11A is the sinus-rhythm activation map. Shown is an area oflate-activation, and the measurement vectors radiating from it, in whichone of the vectors meets the stringent criteria for primary axis (vector8 with AU=0.98 and AG=0.32). Along the primary axis, electricalconduction is slow and uniform during sinus-rhythm. In FIG. 11B is shownthe sinus-rhythm electrogram duration map. The numbers denote theelectrogram duration in milliseconds for each of the gray levels. Ineach gray level, the recording sites have electrogram duration in arange around the number associated with the gray level. The shortestelectrogram duration occurs at the area where the reentrant ventriculartachycardia isthmus forms, as is most often the case in clinical andexperimental cases. Overlapping the electrogram duration map are thelocations of the arcs of conduction block that form during reentry(thick curvy black lines) and the unidirectional arc of conduction blocklocation that forms during a premature stimulus. All of the arcs ofblock partially align with boundaries between areas with disparatesinus-rhythm electrogram duration. The activation map during pacing witha premature stimulus is shown in FIG. 11C.

The activation maps during ventricular tachycardia are shown in FIGS.11D and 11E. Reentry is shown to occur. Although the arcs of conductionblock are functional, and hence shift from cycle-to-cycle as shown fromFIG. 11D to FIG. 11E, the general location is unchanged, and the primaryaxis computed in FIG. 11A still overlies the reentrant circuit isthmusin each case. In FIG. 11F is shown a map made using piecewise linearadaptive template matching (PLATM). These measurements were made duringventricular tachycardia. At each recording site, the PLATM time is theestimated time interval from activation at the local site to activationat the region of the slow conduction zone in the isthmus of thereentrant circuit. Such information is helpful to the clinician duringEP study and radio-frequency ablation therapy to “home-in” on the targetablation site with greater clarity even when activation mapping resultsare unclear. The PLATM map does not rely on activation mapping; hence itcan provide a clear picture of where to ablate when activation mapscannot.

FIG. 12 shows a table of Patient Clinical Data. The patient number, sex,infarct location, time from myocardial infarct to EP study, drugtherapy, and VT cycle length at onset are given. Most of the patientsare male with a median age of approximately 67 years which is inagreement with the national statistics for this malady. As shown in thecolumn, ventricular tachycardia can strike years following the actualmyocardial infarct. Various drug therapies are given to control themalady, but rarely are drug regimens a permanent and optimal therapy forventricular tachycardia. The rapidity of the heartbeat is also shown forventricular tachycardia in each patient. Faster heartbeat (shortercycle) general equates with increased discomfort and even injury to thepatient during periods in which episodic ventricular tachycardia occurs.

This disclosure will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS

First Series of Experiments

Animal (canine) studies were first done to develop the methodology andthe procedure for analysis [17]. Activation maps were constructedaccording to the methodology described in the literature, andcomparisons were made of activation maps of sinus-rhythm versusreentrant ventricular tachycardia. There were special characteristicsthat could be observed in the sinus-rhythm activation maps at thelocation where the isthmus of the reentrant circuit formed duringventricular tachycardia. Namely, the activation wavefront proceeded,during sinus-rhythm, in parallel to but opposite in direction to theactivation wavefront during reentry at the location of the isthmus.Also, during sinus-rhythm, activation there appeared to be relativelyslow compared with other areas of the infarct border zone, and uniformin terms of a relatively constant conduction velocity and a relativelylinear leading edge of the activation wavefront. We believe this is dueto the special tissue electrical properties at this location thatpersist regardless of rhythm type; i.e., full gap-junctionaldissociation throughout the thickness of the border zone [8] and havingthe property of being the area of the border zone with thinnest layer ofsurviving cells [6, 17]. These properties are believed to produce theobserved effects on the activation wavefront during'sinus-rhythm, and toset up the conditions for the isthmus of the reentrant circuit to formthere (i.e., slow and uniform conduction). It was also observed thatadjacent to the area with slow, uniform conduction during sinus-rhythmwhere the isthmus of the reentrant circuit formed, was the region tolast-activate during sinus-rhythm.

To develop a methodology that could quantify the above qualitativeobservations, mathematical calculations were incorporated to compute themean of the last region to activate during sinus-rhythm, and todetermine the linear regression of activation times along lines(measurement vectors) originating at the XY center of thislast-activating region. It was observed that one of the vectors (primaryvector or axis with constraints described elsewhere) would alwaysapproximately align with the long axis of the isthmus of the reentrantcircuit, when it occurred. Hence, it would be possible, based on thismethodology of sinus-rhythm measurements: 1. To predict whether or notreentrant ventricular tachycardia would occur. 2. To determine theapproximate location of the reentry isthmus, and also the direction ofits long-axis.

The methodology was expanded to define the exact shape of the isthmus ofthe reentrant circuit based on sinus-rhythm measurements [17]. Thisinvolved the sinus-rhythm electrogram duration calculation and mapconstructed from it for all sites in the border zone. Based on thelocation of the primary vector or axis, when reentry was predicted tooccur, sites surrounding this location with a difference in electrogramduration between them that was greater than a predetermined value (15milliseconds in papers) were marked on the computerized grid. Thelocations were then connected to encompass the XY location oflast-activation (which is always the origin or tail of the primaryvector) and a distance along the primary vector (taken as 1 centimeterin the sinus-rhythm paper [17]). The methodology to connect the pointswas described elsewhere, and the surface area encompassed by theresulting polygonal shape is the estimated location and shape of theisthmus of the reentrant circuit based on sinus-rhythm measurements.Also described elsewhere, the estimated best line to ablate based on theestimated isthmus location and shape. These procedures were then usedsuccessfully on clinical data acquired with a noncontact probe [17].

A. Materials and Methods

A myocardial infarct was created by LAD ligation in experiments in 54canine hearts and attempts to induce reentry in canines anesthetizedwith sodium pentobarbitol were made 4-5 days later by prematureelectrical stimulation [9]. Bipolar electrograms were recorded from196-312 sites in the epicardial border zone of the anterior leftventricle for 25 experiments with predominantly long-runs of monomorphicreentry (10 beats, mean 181.9 beats), 11 experiments with shortmonomorphic or polymorphic runs (<10 beats, mean 4.5 beats), and 18experiments in which reentry was not inducible. Programmed stimulationfrom the LAD, lateral, base, or center region of the ventricle proceededusing ten S1 stimuli followed by a single premature stimulus. Thepremature coupling intervals were successively shortened on subsequentstimulus trains until reentry was induced. For consistency betweenexperiments, the multi-electrode array was placed on the heart with thesame edge always positioned along the LAD margin. For simplicity, theventricular area where recording sites in the multi-electrode array werelocated was considered to encompass the entire infarct border zone.

Activation maps [9] were created from data obtained from the border zoneduring sinus rhythm, pacing, and reentry, when it occurred. For eachexperiment, the sinus rhythm map was constructed from an arbitrary cycleat the beginning of the experiment prior to programmed stimulation andpace maps were constructed from cycles of the pace train which led toonset of reentry. Reentry maps were constructed from an early cycle ofventricular tachycardia following stabilization of the circuit(long-runs experiments) or for all cycles (short-runs experiments).Inspection of sinus rhythm activation maps in canine hearts in whichreentry was inducible suggested that the isthmus entrance and exit,respectively, tended to form along an axis from the area of last tofirst activity during sinus rhythm. Moreover, the activating wavefrontduring sinus rhythm was observed to advance in parallel to this axis,with uniform conduction velocity, and in the opposite direction toactivation within the isthmus during reentry. To quantify thisphenomenon, the last 10 ms interval during which (5 contiguous sitesactivated was ascertained. The XY-center of this region was computed asthe mean value of the site locations in the X- and Y-directions,referenced to an arbitrary fiduciary point on the computerized electrodegrid. The linear regression of activation times was computed along eightrays originating from the geometric center of this last-activatingregion (45 degree ray separation with orientation such that two of therays were precisely vertical on the grid). The activation times at foursites along each ray (0.8 cm spacing between sites), plus the centersite itself (five sites in all), were used for each regression (rays notentirely on the grid-were excluded from analysis). The ray with highestr² value was termed the primary axis. The regression line slope alongthe primary axis (termed the activation gradient), and the r² value(termed the activation uniformity), were graphed for all experiments asa scatter plot. From the scatter plots, the best linear thresholds toclassify experiments in which reentry could versus could not be inducedwere determined manually for the activation uniformity parameter aloneand for the activation gradient-uniformity parameters in tandem.

The electrogram duration, defined as that contiguous series ofelectrogram deflections with no isoelectric segment of >5 ms duration,encompassing the time of local activation at the recording site duringone cardiac cycle, was also measured for all electrogram recordingsobtained during the same cycle used to construct the sinus rhythmactivation map. The starting and ending points, respectively, wereconsidered to be the beginning and ending times at which contiguouselectrogram deflections arose above the isoelectric level to anamplitude >10% of the maximum electrogram peak. Electrogram duration forall sites was mapped using the same-computerized electrode grid that wasused for activation mapping. The location of the XY-center oflast-activation during sinus rhythm, and the location of reentry arcs ofblock determined from the reentry activation map, were superimposed onthe electrogram duration map computerized grid. Separate means ofelectrogram duration were computed for: 1) sites residing along theprimary axis that were used for its regression equation, 2) all sitesresiding within the area where the isthmus formed, and 3) all sites inthe border zone (including those within the isthmus). The meanelectrogram duration along the primary axis was graphed versus theactivation gradient along the primary axis for all experiments, and theresulting scatter plots were also used to classify experiments in whichreentry could versus could not be induced as described above for theactivation gradient-uniformity scatter plot.

Locations where the difference in sinus rhythm electrogram durationbetween any two adjacent sites (horizontal, vertical, or diagonaldirection) was (15 ms, were marked on the computerized electrogramduration map grid. Selected marks were then connected to form the borderof a contiguous region using the following methodology implemented on adigital PC-type computer: 1. the region must encompass the XY-center oflast-activation and the initial 1 cm of the primary axis extending fromit, 2. marks were connected so as to: a. minimize the maximum distancebetween connections, followed by b. minimize the mean distance betweenconnections, and 3. the inscribed region must have surface area 2.0 cm²(the approximate minimum isthmus surface area that was observed in anyexperiment). The contiguous region so formed (the estimated isthmus) wascompared to the actual location and shape of the reentry isthmus(delineated by connecting the computerized grid locations of block lineendpoints which were superimposed from the reentry activation map) andmean standard error was computed from all experiments. The directiondesignated by the primary axis was considered to be an approximation ofthe direction of activation through the actual isthmus during reentry. Astraight line, called the estimated line for ablation, was then drawnperpendicular to the primary axis from one edge of the estimated isthmusto the other on the computerized grid. The location of the estimatedline for ablation was chosen so as to bisect the estimated isthmus intohalves with equal areas. The percent of the width of the actual reentryisthmus that the estimated-line for ablation spanned was then computedand tabulated.

Significance of quantitative variables was determined using computerizedstatistical procedures (SigmaStat, Jandel Scientific) as follows. Forcomparison of mean activation gradients and mean electrogram durations,the difference in means (t-test) was calculated. For comparison ofisthmus locations, first the XY-center of the estimated isthmus wastaken as the point along the primary axis 1 cm from the origin. Then theactual reentry isthmus location on the computerized grid wasapproximated as the mean XY-location of the four endpoints of the twoarcs of block which bounded the isthmus. For polymorphic experimentswith multiple isthmus locations, the XY-center of the actual isthmuswhich was closest to the estimate was used for statistical comparison.The linear regression of estimated versus actual XY-centers was thencalculated for all reentry experiments. A linear regression was alsocomputed for percent overlap of isthmuses versus heart rate.

B. Results

FIGS. 1A-1D show activation maps for sinus rhythm (FIG. 1A), prematurestimulation (S2) from the center of the border zone (FIG. 1B), andreentry (FIG. 1C), and the electrogram duration map (FIG. 1D) for acanine experiment in which only long-runs of monomorphic reentry with asingle morphology were inducible. Wavefront propagation directionthrough the isthmus during reentry (FIG. 1C) is oriented in parallel butopposite to propagation in the same region during sinus rhythm (FIG.1A). During sinus rhythm (FIG. 1A), the 5 or more last sites to activatewithin a 10 ms interval have activation times between 60-69 ms. Nearestto the XY-center of last-activation (+) is a site which activates attime 91 ms. The locations used to determine the linear regression, whichincluded this site, are denoted by their activation times and the raysare numbered from 1-8. The accompanying table shows activationuniformity and gradient for each ray. The ray with greatest activationuniformity (the primary axis) is ray 1 (r²=0.97). The primary axis haslowest activation gradient (0.41 m/s) and is approximately parallel tothe isthmus long axis. The block lines forming during prematurestimulation and during reentry partially align between areas of largedisparity in sinus rhythm electrogram duration (for simplicity, onlyreentry arcs of block are superimposed on the electrogram duration map).Based on the isthmus estimation methodology, boundary points of theestimated isthmus are given by cross-hatched circles (FIG. 1D). Thisarea partially overlaps the actual reentry isthmus whose boundaries areformed by the superimposed arcs of block. Examples of electrograms withdiffering electrogram duration are shown (insert, FIG. 1D); within mostof the reentry isthmus region, electrogram duration was relativelyshort. Other long-runs experiments had similar properties to FIGS.1A-1D. Along the primary axis for all long-runs experiments, meanactivation uniformity and gradient was 0.97 (0.01 and 0.67 (0.04 m/s,respectively. The mean sinus rhythm electrogram duration for sitesresiding within the isthmus area for all experiments was 24.2 (0.4 ms(mean of 18.4(2.2 sites per isthmus) which was significantly lower(p<0.001) than for the border zone as a whole (34.1 (0.7 ms). For mostlong-runs experiments including that of FIG. 1, wavefront orientationduring sinus rhythm was approximately parallel to the primary axis;therefore the activation uniformity and gradient along the primary axiswas proportional to conduction uniformity and velocity, respectively,along the same axis.

FIGS. 2A-2D show maps from an experiment in which only short-runs of 3-8beats of monomorphic reentry could be induced. The sinus rhythmactivation map (FIG. 2A) shows the region where the isthmus forms(shaded). The primary axis (r²=0.96) approximately aligned with theisthmus long axis and extended from late-to early-depolarizing regionsduring sinus rhythm (upward vertical direction originating at the larger50 ms isochrone). For the reentry episode of FIGS. 2A-2D, activationmaps of reentry beats 1-2 were similar (second beat is shown in FIG.2B). The reentry arcs of block partially align at edges between areaswith large disparity in electrogram duration (FIG. 2D). Mostlyshort-duration sinus rhythm electrograms are present at the reentryisthmus location. On the third reentry cycle, the left arc suddenlyshifted inward (dotted in FIG. 2C) to align with a different edge oflarge disparity in electrogram duration (FIG. 2D). On the next(termination) cycle, the activating wavefront blocked at the narrowestwidth of the reentry isthmus (not shown). The boundary points of theestimated isthmus are shown (FIG. 2D, hatched circles) and as in FIGS.1A-1D, they partially overlap the actual isthmus location. Othermonomorphic short-runs experiments had similar properties to FIGS.2A-2D. Along the primary axis for all short-runs experiments, meanactivation uniformity and gradient was r²=0.94(0.01 and 0.79(0.12 m/s,respectively. Also for all short-runs experiments, mean sinus rhythmelectrogram duration at the isthmus location was 22.7 (0.7 ms (mean of9.9 (2.0 sites per isthmus) which was significantly lower (p<0.05) thanfor the border zone as a whole (28.8 (0.6 ms). The mean sinus rhythmelectrogram duration throughout the border zone was significantly lessin short versus long-runs experiments (p<0.05).

For experiments lacking reentry, activation uniformity and gradientalong the primary axis were r²=0.93(0.02 and 1.22(0.08 ms, respectively,and the mean electrogram duration throughout the border zone was31.3(0.5. In most experiments lacking reentry, the wavefront propagationdirection during sinus rhythm did not align with the primary axis.

FIG. 3A shows a scatter plot of activation uniformity and gradient alongthe primary axis during sinus rhythm for each experiment. Shown are thebest threshold to classify experiments using activation gradient alone(dotted line), and for activation gradient-uniformity in tandem (dashedline). In 24/25 experiments with long-runs of reentry (solid-circles),and 9/13 primary axes present in 11 short-runs experiments(solid-triangles), each threshold predicted that reentry could beinduced. In 15/18 experiments lacking reentry (open-circles), theactivation gradient threshold alone predicted that reentry could not beinduced; prediction improved to 17/18 when the activationgradient-uniformity threshold was used. The difference in means in theactivation gradient parameter between each of the three groups wassignificant (p<0.001). FIG. 3B shows a scatter plot of the meanelectrogram duration versus activation gradient computed along theprimary axis for each experiment. For comparison the best activationgradient threshold is shown (dotted line; same as in FIG. 3A). The bestthreshold for electrogram duration/activation gradient in tandem (dashedline) can be used to correctly classify experiments into those with orwithout inducible reentry with the same accuracy as the activationgradient-uniformity threshold of FIG. 3A. In FIG. 3B, the pointsrepresenting experiments with short-runs of reentry (solid-triangles)tend to form a curvilinear boundary separating points representingexperiments with long-runs of reentry versus no reentry.

FIGS. 4A-4Y show the estimated reentry isthmus (region with grid lines),the estimated wavefront direction through it (arrow), the estimated bestline for ablation (dashed line), and the actual location of reentry arcsof block (thick curvy lines) for each experiment with long-runs ofreentry. FIG. 4A-4Y are ordered from shortest to longest reentrycycle-length. Shown in FIG. 4W are estimates for the FIGS. 1A-1Dexperiment (boundary points denoted in FIG. 1D). In two experiments(FIGS. 4O and 4Y), two reentry morphologies occurred and arcs of blockare shown for each. For all long-runs experiments, the estimated reentryisthmus surface area mostly overlapped with actual isthmus location(mean overlap 71.3(3.2%), which was independent of heart rate (p=0.25).The XY-centers of the estimated and actual reentry isthmus were linearlycorrelated (X:r²=0.77, Y:r²=0.60; p<0.001). Also, the estimated bestline for ablation extended across most of the width of the actualreentry isthmus (mean 88.2%).

In FIGS. 5A-5K the estimated isthmus parameters are shown forexperiments with short-runs of reentry (polymorphic in FIGS. 5A-5E andmonomorphic in FIGS. 5F-5K; separately ordered based on cycle-length).In three polymorphic experiments (FIGS. 5A-5C), only a singlelate-activating region was detected in the sinus rhythm activation mapalthough there were isthmuses at multiple locations during reentry. InFIGS. 5D-5E, two estimated isthmuses are shown because there were twolate-activating regions and therefore two primary axes during sinusrhythm. The estimates for the experiment of FIGS. 2A-2D are shown inFIG. 5F. For all short-runs experiments, the estimated reentry isthmussurface area partially overlapped actual isthmus location (mean overlap58.6 (9.0% for monomorphic experiments, 25.7 (6.3% for polymorphic, and43.6 (7.5% overall), which was independent of heart rate (p=0.45). TheXY-centers of the estimated and actual reentry isthmuses were linearlycorrelated (X:r²=0.78, Y:r²=0.81; P<0.001). Also, the estimated bestline for ablation extended across more than half the width of the actualreentry isthmus (mean 55.4%).

C. Discussion

1. Electrical Properties at the Isthmus Location

The results of this study suggest that the area over which the primaryaxis extends during sinus rhythm has special distinguishing electricalcharacteristics for experiments in which reentry was inducible versusthose lacking inducibility. In experiments with monomorphic reentry, theprimary axis often overlapped the actual isthmus location, which is thatarea of the border zone with thinnest layer of surviving myocytes [6-7]and having full-thickness gap-junctional disarray [8]. Disarray ofgap-junctional intercellular connections are also present at the isthmusformation area in reentrant ventricular tachycardia in humans [10].Uniformity of gap-junctional disarray throughout the region [8] may havebeen responsible for the uniform activation gradient and thereforeconduction velocity uniformity (since the activating wavefront tended topropagate in parallel to the primary axis). Sinus rhythm electrogramduration tended to be short within the isthmus formation area, andlonger just outside it, resulting in large differences in electrogramduration at isthmus edges that were used to draw boundary points.Electrical activation at depth is often asynchronous with surfaceactivation [11]; therefore, reduction of electrical activity at depth,due to thinness of the layer, may have acted to shorten electrogramduration within the isthmus region.

In many experiments, conduction was impeded at border areas betweenregions with a large disparity in electrogram duration, both duringpremature stimulation and during reentry (FIGS. 1B-D and 2B-D). Suchborder areas, or discontinuities, between regions with differingelectrical properties are marked by presence of increased axialresistivity [12]. Under normal conditions, depolarizing current issufficiently coupled across such discontinuities to maintainpropagation; however, current available for activation is reduced duringpremature stimulation and reentry, causing slow conduction or block[12]. An arbitrary threshold of 15 ms difference in electrogram durationwas used to mark areas where arcs of block would form. However,disparity in sinus rhythm electrogram duration was not always largealong the entire length where block lines actually formed (FIGS. 1D,2D). This may have resulted from diffraction effects in which wavefrontcurvature, as it traverses a small aperture between impassableobstacles, increases beyond a critical value so that propagation ceases[13]. Boundary points between regions with large disparity inelectrogram duration would act as nearly impassable obstacles because oftheir high axial resistivity, whereas block would also occur alongconnecting segments between them, although disparity in electrogramduration is smaller, with presumably lowered axial resistivity, due tothe aperture effect.

2. Clinical Significance of the Study

There is abundant evidence that ventricular tachycardia in humanpatients is often caused by reentrant excitation [1, 2, 5, 14]. Thereare several similarities between clinical observations and themeasurements of electrical activation during sinus rhythm in caninehearts with and without inducible reentry. Clinical studies suggest thatthe extent of abnormal activation and number of fractionatedelectrograms tends to be greater in patients with sustained reentrycompared with unsustained reentry [14], in accord with the result ofthis study that mean sinus rhythm electrogram duration throughout theborder zone was significantly greater for experiments with long-runs ofreentry versus short-runs of reentry (p<0.05). Also, clinical findingssuggest that disrupted and delayed endocardial activation [14,15] andprolonged, fractionated electrograms during sinus rhythm [14] candistinguish patients with reentrant ventricular tachycardia from thosewith normal ventricles and those of prior infarction without reentry. Inthe present study, although the isthmus area tended to have short sinusrhythm electrogram duration, areas adjacent to it within the reentrycircuit area often had much longer electrogram duration (FIGS. 1-2),consistent with clinical findings. Additionally, the last-activatingregion of the border zone during sinus rhythm tended to reside inproximity to the reentry isthmus in both clinical studies [2, 3] and inthe present study. These similarities suggest that it may be possible toapply the methodology described herein to targeting of clinical ablationsites; for example using a non-contact mapping system [3]. However,differences in infarct age, the intracellular matrix, border zonelocation, and action potential characteristics may cause clinical datato vary significantly from canine heart data used in the present study[6], and therefore necessitate modification of the quantitativetechniques.

Imprecision in activation mapping due to limited spatial resolutionand/or ambiguous time of local activation at any given recording sitewill affect both the activation gradient measurements and localizationof arcs of block. Use of a different threshold for electrogram durationmeasurements could alter the precise locations of boundary points. Bothmultiple deflections (fractionation) and a single wide deflection wereconsidered indicative of abnormal cell presence and wavefrontimpediment; however, anatomic and histologic correlation to support thishypothesis was not performed in this series of experiments, which is animportant limitation of this study. The results described herein forfunctional reentrant circuits in a canine model may not be fullyapplicable to reentrant ventricular tachycardia occurring in humans,where anatomical arcs of block can occur more frequently [5].

D. References for First Series of Experiments

-   1. Stevenson W G, Friedman P L, Kocovic D Z, et al. Radiofrequency    catheter ablation of ventricular tachycardia after myocardial    infarction. Circulation 1998; 98:308-314.-   2. Harada T, Stevenson W G, Kocovic D Z et al. Catheter ablation of    ventricular tachycardia after myocardial infarction: relationship of    endocardial sinus rhythm late potentials to the reentry circuit.    JACC 1997; 30:1015-1023.-   3. Schilling R J, Davies D W, Peters N S. Characteristics of sinus    rhythm electrograms at sites of ablation of ventricular tachycardia    relative to all other sites: a non-contact mapping study of the    entire left ventricle. JCE 1998; 9:921-933.-   4. Gardner P I, Ursell P C, Fenoglio J J Jr. et al.    Electrophysiologic and anatomic basis for fractionated electrograms    recorded from healed myocardial infarcts. Circulation 1985;    72:596-611.-   5. Ellison K E, Stevenson W G, Sweeney M O et al. Catheter ablation    for hemodynamically unstable monomorphic ventricular tachycardia.    JCE 2000; 11:41-44.-   6. Wit A L, Janse M J. Basic mechanisms of arrhythmias. In: Wit A L    and Janse M J, eds. The ventricular arrhythmias of ischemia and    infarction. New York, N.Y.: Futura; 1993:1-160.-   7. Scherlag B J, Brachman J, Kabell G et al. Sustained ventricular    tachycardia: common functional properties of different anatomical    substrates. In Zipes D P, Jalife J, eds. Cardiac electrophysiology    and arrhythmias. Orlando Fla.: Grune and Stratton; 1985:379-387.-   8. Peters N S, Coromilas J, Severs N J et al. Disturbed connexin43    gap junction distribution correlates with the location of reentrant    circuits in the epicardial border zone of healing canine infarcts    that cause ventricular tachycardia. Circulation 1997; 95:988-996.-   9. Dillon S M, Allessie M A, Ursell P C et al. Influences of    anisotropic tissue structure on reentrant circuits in the epicardial    border zone of subacute canine infarcts. Circulation Research 1988;    63:182-206.-   10. Smith J H, Green C R, Peters N S et al. Altered patterns of gap    junctional distribution in ischemic heart disease: an    immunohistochemical study of human myocardium using laser scanning    confocal microscopy. Am J Path 1991; 139:801-821.-   11. Miller J M, Tyson G S, Hargrove W C III et al.    Arrhythmias/Pacing/Surgical correction: effect of subendocardial    resection on sinus rhythm endocardial electrogram abnormalities.    Circulation 1995; 91:2385-2391.-   12. Spach M S, Miller W T III, Dolber P C et al. The functional role    of structural complexities in the propagation of depolarization in    the atrium of the dog. Circulation Research 1982; 50:175-191.-   13. Cabo C, Pertsov A M, Baxter W T et al. Wave-front curvature as a    cause of slow conduction and block in isolated cardiac muscle.    Circulation Research 1994; 75:1014-1028.-   14. Josephson M E Zimetbaum P, Huang D. Pathophysiologic substrate    for sustained ventricular tachycardia in coronary artery disease.    Jap Circ J 1997; 61:459-466.-   15. Pogwizd S M, Corr P B. Reentrant and nonreentrant mechanisms    contribute to arrhythmogenesis during early myocardial ischemia:    results using three-dimensional mapping. Circulation Research 1987;    61:352-371.-   16. Blanchard S M, Walcott G P, Wharton J M, et al. Why is catheter    ablation less successful than surgery for treating ventricular    tachycardia that results from coronary artery disease? PACE 1994;    17:2315-2335.

17. E J, Tosti A C, Scheinmann M M. Relationship between Sinus RhythmActivation and the Reentrant Ventricular Tachycardia Isthmus.Circulation. 2001; 104: 613-619.

Second Series of Experiments

A. Method

1. Clinical Recordings and Data Reduction

Data was acquired using a non-contact mapping catheter (EndocardialSolutions, Inc., St. Paul, Minn.) during clinical electrophysiologicstudy of patients with postinfarction ventricular tachycardia who wereundergoing treatment with radiofrequency catheter ablation. Thenon-contact catheter is positioned in the left ventricular cavity wheresignals are acquired and digitized, and using inverse solutionmathematics, unipolar electrograms that are present across theendocardial surface are reconstructed at up to 3,360 sites [1-2]. Theclinical procedure to localize the non-contact probe within theendocardial cavity and to record data, and also the physicalspecifications of the non-contact catheter, have been described indetail elsewhere [1-2]. This study was done retrospectively in 14consecutive unselected patients (FIG. 13) in which ventriculartachycardia was suspected to be caused by a reentrant circuit.Approximately 20 cycles each of sinus-rhythm, ventricular pacing,ventricular tachycardia, and the pacing train leading to tachycardiaonset, were extracted from the data for further analysis of 256uniformly distributed endocardial sites (˜0.5 cm spatial resolutionbetween sites). The digital sampling rate was 1 kHz and the band passfrequency range was 0.5-500 Hz during the data acquisition andmathematical reconstruction process. The 3-dimensional locations of the256 sites on the virtual endocardial surface (16 virtual sites alongeach of 16 longitudinal lines around the inside of the endocardialcavity) were translated to a 2-dimensional computerized grid using anEckert VI projection, which is a pseudocylindrical map in which thecentral meridian and all parallels are at right angles, and all othermeridians are sinusoidal curves. In this type of cartographicprojection, some shape distortion occurs at the poles.

Activation maps of sinus-rhythm, ventricular pacing, and ventriculartachycardia were made by first marking activation times of the unipolarelectrogram signals. Computer software was used to manually determinethe point of sharpest slope in the signal [10], or the center point ifmultiple deflections with sharp slopes were present. Activation timesduring a selected cardiac-cycle were then printed on the 2-dimensionalcomputerized map grid. Isochrones were set at 10-40 ms intervals, andarcs of conduction block separated sites in which activation differedby >40 ms and where wavefronts on opposite sides of the arcs moved indifferent directions [10]. The arcs were drawn using a cubic splineinterpolation program (PSI-Plot Ver. 4, 1995 PSI) which is based on apolynomial equation that minimizes the straight-line distance to a setof boundary points. Although the actual spacing between sites was ˜0.5cm, the spline interpolation function generates a curved line that wassuperimposed on the computerized grid with 0.1 mm precision. Theelectrogram duration, defined as that contiguous series of electrogramdeflections with no isoelectric segment of >5 ms duration, encompassingthe time of local activation at the recording site during one cardiaccycle, was also measured for all electrogram recordings obtained duringthe same cycle used to construct the sinus-rhythm activation map [6].The starting and ending points, respectively, were considered to be thebeginning and ending times at which contiguous electrogram deflectionsarose above the isoelectric level to an amplitude >10% of the maximumelectrogram peak. Electrogram duration was mapped using the sameautomated, 2-dimensional computerized electrode grid that was utilizedfor activation mapping.

2. Sinus-Rhythm Electrogram Analysis

These measurements were undertaken to determine if the isthmus of thereentrant circuit causing tachycardia could be located from analysis ofelectrograms obtained during sinus-rhythm. The hypothesis to be testedwas that in clinical non-contact activation maps of sinus-rhythm, as incanine study activation maps [6], conduction was relatively slow anduniform where the isthmus formed. To quantify this phenomenon, the last10 ms interval during which 5 contiguous sites activated was determined.The XY-center of this region was computed as the mean value of the sitelocations in the X- and Y-directions, referenced to an arbitraryfiduciary point on the computerized electrode grid [6]. A linearregression of activation times was computed along eight rays originatingfrom the geometric center of this last-activating region (45 degree rayseparation with orientation such that two of the rays were preciselyvertical on the grid). The activation times at four selected sites alongeach ray (˜0.5 cm spacing between sites), plus the center site itself(five sites in all), were used for each regression. The ray withgreatest regression coefficient (r²>0.9) and a steep activation gradient(regression line slope<0.6 m/s), if present, was termed the primary axis[6]. If none of the rays met the threshold uniformity and gradientcriteria, then the XY centers of any other late-activating regions onthe endocardial surface were computed and the process of searching for aprimary axis meeting the above threshold criteria was repeated. If noray originating at a late-activating region met the criteria, then theray originating from the last-activating region with the greatestregression coefficient was taken as the primary axis. Presence of aprimary axis meeting the threshold criteria was considered to indicatethat an endocardial reentry circuit would be detectable in theventricular tachycardia activation map, and its location and orientationwere considered to approximate the isthmus location and wavefrontpropagation direction through the isthmus during reentry. Whereas,absence of a primary axis meeting the threshold criteria was consideredto indicate that a complete endocardial reentry circuit would not occurduring tachycardia.

For cases in which the primary axis met the threshold criteria, theisthmus shape was estimated as follows. First areas of the sinus-rhythmelectrogram duration map in which the difference in electrogram durationbetween any two adjacent sites was 15 ms was marked on the computerizedgrid as described previously [6]. Selected marks around the primary axiswere connected by computer methodology so as to form the border of acontiguous region which minimized the distance between the boundarypoints while maintaining the surface area of the enclosed section abovea minimum constraint [6]. The contiguous region so formed was termed theestimated isthmus. The percent overlap, on the computerized grid, of thesurface area in which the actual isthmus determined by activationmapping was overlapped by the estimated isthmus, divided by the totalsurface area of the actual isthmus, was computed and tabulated. Astraight line, called the estimated best ablation line, was then drawnon the computerized grid, perpendicular to the primary axis, and fromone edge of the estimated isthmus to the other so as to bisect it intohalves with equal areas. The percent that the estimated best ablationline spanned the actual reentry isthmus determined by activation mappingwas also computed and tabulated.

3. Ventricular Tachycardia Electrogram Analysis.

These measurements were undertaken to determine whether, as in caninemodel studies, tachycardia cycle-length is related to reentry isthmusgeometry [7], and if the SCZ could be pinpointed using the electrogramacquired from any recording site in the endocardium [9]. Simple linearrelationships approximated the reentry isthmus geometric shape [7-8].The isthmus length, width, and narrowest-width were first linearized(skeletonized) from the reentry activation map computerized grids asfollows (see result in FIGS. 3A and 3B). First the endpoint-to-endpointdistance on the computerized grid was determined for each of the twoarcs of block bounding the isthmus. The average of these two lengths wastaken as the skeletonized isthmus length. The distance between theendpoints of the arcs of block at the isthmus entrance and also at theisthmus exit was then determined. The average of these two distances wastaken as the skeletonized isthmus width. The minimum distance betweenthe two arcs of conduction block was termed the skeletonizednarrowest-width of the isthmus.

In cases where tachycardia cycle-length changed gradually in onedirection (either prolongation or shortening) by >5 ms during the ˜20beat recording interval, isthmus skeletonized parameters were computedand tabulated at the extremes in cycle length [8]. The correlationrelationships of skeletonized isthmus parameters with tachycardiacycle-length, and with changes in cycle-length, were calculated andtabulated as described elsewhere [7-8]. In cases with gradualcycle-length change in one direction, a method termed piecewise-linearadaptive template matching (PLATM) was also used to approximate thetiming from activation at each virtual recording site on the leftventricular endocardium to activation at the SCZ center [9]. Theparadigm is based on measurement of phase shifts in the far-fielddeflections of the extracellular signal, which are reflective ofalterations in SCZ conduction velocity [8-9]. The mean and standarderror difference between the time of SCZ center activation computed withPLATM, referenced to activation at the local recording site, and thesame activation interval determined by activation mapping, wascalculated. All statistical computations were made using a commercialcomputer program (SigmaStat V2.0, Jandel Scientific).

B. Results

1. Geometry of the Reentry Circuit

Non-contact activation maps revealed that tachycardias in 11/14 patientswere associated with an endocardial reentry circuit having a “figure-8”conduction pattern [5]. Examples from four cases are shown in FIGS.8A-8D. The north and south poles of the 3-dimensional electrodedistribution from the non-contact data are represented, respectively, bythe top and bottom edges of the 2-dimensional grids in FIGS. 8A-8D. Theleft and right edges of the grids represent the place where the3-dimensional electrode distribution was separated at a line oflongitude; these edges are actually continuous with one another in3-dimensional space. In each map, the wavefront courses through thereentry isthmus, which is bounded by arcs of conduction block (thickcurvy black lines), with arrows denoting the direction of wavefrontpropagation. At the isthmus exit, in each case the wavefront bifurcatesand travels as separate wavefronts outside the arcs of conduction blockand away from the isthmus. In FIG. 8A, an arc of conduction blockextends outward across the left edge of the map and continues inwardfrom the right edge. In FIGS. 8A-8D, the separate wavefronts coalesce atthe isthmus entrance. Cycle-length at onset for all tachycardias aregiven in FIG. 12. The mean cycle-length at onset for the 11 patientswith reentrant tachycardia was 331 ms, and the mean skeletonized isthmuslength, width, and narrowest-width were 5.5 cm, 4.7 cm, and 2.2 cm,respectively.

2. Isthmus Characterization from Sinus-Rhythm Electrogram Analysis

Sinus-rhythm electrogram analysis was able to localize the isthmus ofthe reentrant circuit. In FIGS. 9A-9B is given an example ofsinus-rhythm electrogram analysis measurements (patient 5 from FIG. 12).Shown are the sinus-rhythm (FIG. 9A), premature stimulation (FIG. 9C),and reentry activation maps (FIG. 9D). During sinus-rhythm, the XYcenter of last-activation is denoted at the site marked “52”, and theeight rays projecting from it that were used to make measurements ofactivation gradient and uniformity are shown in FIG. 9A, with somewrap-around to the other side of the grid). Ray 2 is the primary raybecause it has greatest activation uniformity (r²=0.99) and steepestgradient (∇=0.48 m/s) (see table in FIG. 9A). Shown in FIG. 9B is theelectrogram duration map (examples of the endpoints in duration forselected electrograms are given in the inset). The primary ray islocated within a region of short electrogram duration, and the estimatedisthmus and estimated best ablation line (see Methods section) aredenoted by the dashed polygon and dotted line, respectively, overlaid onthe map grid (FIG. 9B). During premature stimulation (FIG. 9C), thelarge region with relatively late activation, bordered by a 60 msisochrone, approximately coincides with an area of long sinus-rhythmelectrogram duration (>60 ms, lower left in FIG. 9B). The locations ofthe arcs of conduction block that form during tachycardia, denoted bythick curvy lines in FIG. 9D, can be observed to partially align withboundaries between regions of greatly differing sinus-rhythm electrogramduration (FIG. 9B). The actual reentry isthmus location and shapedetermined by activation mapping (FIG. 9D) can be observed toapproximately coincide with the reentry isthmus location and shapeestimated from sinus-rhythm electrogram analysis (FIG. 9B). In each ofthe 11 patients in which a complete endocardial reentry circuit could bemapped (patients 1-10 and 12), a primary axis meeting the thresholdcriteria given in the Methods overlapped the reentry isthmus locationand was in parallel with the isthmus long-axis. Whereas, a primary axismeeting the threshold criteria was absent in all 3 patients lacking acomplete endocardial reentry circuit (patients 11 and 13-14).

In FIG. 10 the overlap of estimated isthmus (area enclosed by dashedline) versus the actual isthmus determined by activation mapping (graysurface bounded by superimposed arcs of block indicated by thick blacklines) is shown for all 11 patients with “figure-8” reentry. Thelocation and direction of the primary axis is given by the arrow.Frequently there is a close overlap (patients 1-2, 5-8) and theestimated best ablation line (dotted line) spans most or all of theactual isthmus width (patients 1-3, 5, 8-9, and 11). For all 11patients, the mean overlap of the estimated isthmus with the actualisthmus was 74.2% and the estimated best ablation line spanned theactual reentry isthmus width by a mean of 83.1%.

3. Isthmus Characterization from Ventricular Tachycardia

Electrogram Analysis

FIGS. 11A-11D show an example of how PLATM9 can be used to measure thetime interval from local to SCZ activation (patient 9 from FIG. 12). Theactivation and electrogram duration map of sinus-rhythm are shown inFIGS. 11A-11B, and an activation map during pacing, and duringtachycardia for short and long cardiac-cycles are shown in FIGS. 11C-11Erespectively. The ray with the most uniform activity and steep gradientis ray 8 (∇=0.32, r²=0.98) (FIG. 11A). Electrogram duration is shortwithin the area where the isthmus forms (FIG. 11B). During a paced beatwith a premature coupling interval, an arc of block forms (thick blackline, FIG. 11C) and is coincident with a sharp transition in electrogramduration (location denoted by dashed line in FIG. 11B). Twoapproximately parallel arcs of conduction block (thick black lines)reside near the center of the grid during reentry (FIGS. 11D-11E). Thelocations of the arcs in D are also coincident with a sharp transitionin electrogram duration (denoted by solid line in FIG. 11B). As in theexample of FIG. 11, the isthmus has narrowed and the arcs of conductionblock have shortened in length when cycle-length prolongs from FIG. 11Dto 11E. From FIG. 11D to 11E, cycle-length prolongs from 398 to 404 msand the wavefront decelerates at the SCZ (isochrones are more closelyspaced in FIG. 11E). In the PLATM map (FIG. 11F) isochrones delineate 35ms time intervals. PLATM times in the range (35 ms, meaning that theestimated time interval x from local to SCZ activation is −35 ms<×<35ms, are centered near the SCZ at the narrowest span of the isthmus (FIG.11F). The PLATM isochrones increase negatively in the direction distalto the SCZ in the circuit (meaning that SCZ activation has occurredprevious to local activity) and PLATM isochrones increase positively inthe direction proximal to the SCZ (meaning that SCZ activation occursfollowing local activity). Overall for the 5 cases in which a protractedinterval of cycle-length change occurred during tachycardia, PLATMestimated the time interval from local to SCZ activation with a meanerror of 19.4 ms.

C. Discussion

In this study it was determined that in the tachycardias of a selectgroup of patients with endocardial reentry circuits, shape and length ofarcs of conduction block bounding the isthmus of the figure-8 reentrycircuit can change according to cycle-length, and that methods toanalyze sinus-rhythm and ventricular tachycardia electrograms can beuseful to discern the location and shape of circuit features without theneed to construct reentry activation maps. The implication of thesefindings for improvement of clinical mapping procedures is nowdiscussed.

1. The Reentry Isthmus Characterized by Sinus-Rhythm ElectrogramAnalysis

In all 11 patients in which a complete endocardial reentry circuit wasdiscernable in the ventricular tachycardia activation maps, a primaryaxis meeting the threshold criteria given in the Methods overlapped thereentry isthmus location and was in parallel with its long-axis. (seeFIGS. 9A and 11A). Presence of gap-junctional remodeling between cellsextending the full thickness of the infarct border zone at the isthmusregion [11] may be responsible for the reduced conduction velocity andincreased uniformity of conduction that was measured along the primaryaxis in patients with complete endocardial reentry circuits. In the 3patients lacking a complete endocardial reentry circuit, no primary axismeeting threshold criteria was present, suggesting that a circuit wasunsustainable either because full-thickness gap-junctional remodelingwas absent or because it was of insufficient surface area to support areentrant circuit along the endocardial surface. These findings were inaccord with canine model studies in which a similar methodology was used[6].

The arcs of conduction block which formed during premature stimulationand during reentry tended to overlap lines of sharp transition insinus-rhythm electrogram duration (see FIGS. 9B and 9D, FIGS. 11B, 11Cand 11D). Such boundary areas may separate regions with discontinuouselectrical properties characterized by an increased effective axialresistivity [12], which would account for the slow conduction or blockthat was observed to occur in these regions during premature stimulationand during tachycardia. Steep transition in sinus-rhythm electrogramduration also occurred elsewhere in the infarct border zone (FIGS. 9Band 11B), and in a canine infarct model, unidirectional arcs ofconduction block can also form at these regions of the border zoneduring premature stimulation [6]. However, it is only at the isthmusformation region, where activation during sinus-rhythm was measured tobe slow and uniform, that there is most likely to be sufficient delayfollowing premature stimulation, formation of the unidirectional arc ofconduction block, and wavefront travel around the arc, so that there isrecovery of excitability and genesis of reentry. Elsewhere in theinfarct border zone where conduction is more rapid, the time forrecovery of excitability is insufficient and reentry cannot occur.

2. The Reentry Isthmus Characterized by Ventricular TachycardiaElectrogram Analysis

The findings presented herein are consistent with previous studiesshowing that postinfarction ventricular tachycardia in patients withcoronary artery disease is often caused by a reentrant circuit with“figure-8” pattern of conduction [1-2,4]. Although in some examples,extended arcs of conduction block were present away from the reentryisthmus (FIGS. 8A-8D), in most cases the basic pattern of activityduring tachycardia was a relatively simple “figure-8” circuit.Conduction velocity was slow within the SCZ and tended to coincide withthe narrowest-width of the isthmus, which may be related to a reducedcurrent available for activation there since the isthmus is narrowed andthe propagating impulse exits to a distal expansion [13-14]. In cases ofgradual, protracted cycle-length change in one direction duringtachycardia (prolongation or shortening), portions or all of the reentryarcs of block shifted in location; hence these segments were functionalin nature. When cycle-length prolonged, the arcs of block shortened atthe ends. However, the isthmus narrowest-width was a permanent fixturein the sense that arcs of block always bounded it, albeit shifts in thedistance between the arcs occurred when conduction velocity changed inthe SCZ. All of these findings are in accord with canine model studiesin which electrogram analyses were used [6-9].

3. Relevance of Results to Clinical Catheter Ablation of VentricularTachycardia

The results of analysis of sinus-rhythm electrograms suggests thepossibility that the reentrant circuit isthmus can be located withoutthe necessity for induction of ventricular tachycardia; however, thishypothesis requires further testing. The results of tachycardiaelectrogram analysis described in this study have a number ofimplications for ablation of tachycardia. That the ends of the arcs werenot permanent fixtures during periods of reentry cycle-length changeoffers a possible explanation as to why radiofrequency catheter ablationmay stop tachycardia that is induced during clinical electrophysiologicstudy, but tachycardia is sometimes reinducible thereafter [4]. Ifwavefront deceleration occurs in the SCZ and there is no other change inconduction velocity around the circuit, the spatial excitable gap [15]will increase outside the SCZ. Hence, there will be increased time forrecovery of excitability away from the SCZ, which will mostly affect theends of the functional arcs of conduction block, because the cells thereare closest to having recovered excitability [5] Therefore, if anablation lesion is created near the ends of the arcs of conduction blockand cycle-length is volatile, it may prevent successful passage of theelectrical impulse through the diastolic region at certain (shorter)cycle-lengths when the arcs are relatively long (FIG. 11D), becausethere is less time for recovery of excitability. However at other(longer) cycle-lengths when the arcs are shorter in length (FIG. 11E),the lesion would then be exterior to the isthmus so that the impulsecould successfully bypass it, causing reentry to persist.

Furthermore, even when ablating toward the center of the diastolicregion, since isthmus width can vary with cycle-length when arcs ofconduction block are functional, an ablation lesion that scarcely spansthe isthmus at longer cycle-lengths when it is narrow may not span it atshorter cycle-lengths when it is wider, thereby allowing the impulse topropagate around the lesion and tachycardia to persist. Indeed, it hasbeen reported that the ablation lesion sometimes acts to prolongtachycardia cycle-length but not stop tachycardia, as would be expectedif the wavefront were impeded but not blocked by an ablation lesion thatdid not fully span the isthmus width over all possible tachycardiacycle-lengths [16]. At present it is unknown how tachycardiacycle-length, functional arcs of conduction block, and ablation lesionlocation dynamically interact, a subject of future research. However, toensure that the lesion entirely spans the isthmus for the duration oftachycardia even when the circuit is changing dynamically, it may beprudent to ablate across the isthmus at its narrowest-width, which islikely to be a permanent fixture during tachycardia, and for theablation lesion to transect the isthmus to greater than its actual spanduring the mapped cycle, since width may increase should cycle-lengthshorten. Although changes in wavefront speed within the SCZ may notalways occur naturally during tachycardia, administration of drugspreferential to the area [17] may specifically alter SCZ activation sothat the region can still be localized using electrogram analyses.

The translation of the 3-dimensional virtual electrode array locationonto the 2-dimensional grid causes some distortion in the shape of thereentry isthmus and the pattern of activation. The mathematicalreconstruction process is most accurate at the equatorial regions of thenon-contact catheter; circuits with components near the polar regionsare likely to be less accurately represented in the activation maps[1-2]. However, the electrogram analyses described herein were relativemeasurements and hence by reverse distortion, parameters are correctableto the original 3-dimensional space. A relatively low spatial resolutionof recording electrodes was used in the study (˜0.5 cm spacing). Higherspatial resolution can be obtained using the non-contact catheter [1-2];however, analysis complexity would increase. The signal strength fromthe endocardial surface is much greater during systole than diastole[1-2]; thus diastolic components of the reconstructed electrograms areof low amplitude and diastolic activation times are more difficult todiscern, introducing some degree of error into the measurements. In thepresent study, the estimated isthmus location and shape were notcompared with the locations of sites in which concealed entrainmentoccurred during pace mapping [4], nor with the locations of sites inwhich ablation caused termination of tachycardia without recurrence;however, a confirmatory study of this type is planned for the future.Such information might also be useful to determine whether electrogramanalyses can predict where to best ablate to stop tachycardia when acomplete endocardial reentry circuit is absent. Although the notion ofan estimated best ablation line was introduced during this retrospectiveanalysis, testing of such must be reserved for a future, prospectivestudy.

D. References for Second Series of Experiments

-   1. Schilling R J, Peters N S, Davies D W. Simultaneous endocardial    mapping in the human left ventricle using a non-contact catheter.    Circulation 1998;98:887-898.-   2. Schilling R J, Peters N S, Davies D W. Feasibility of a    non-contact catheter for endocardial mapping of human ventricular    tachycardia. Circulation 1999; 99:2543-2552.-   3. Blanchard S M, Walcott G P, Wharton J M, et al. Why is catheter    ablation less successful than surgery for treating ventricular    tachycardia that results from coronary artery disease? PACE    1994;17:2315-2335.-   4. Stevenson W G, Friedman P L, Kocovic D, et al. Radiofrequency    catheter ablation of ventricular tachycardia after myocardial    infarction. Circulation 1998; 98:308-314.-   5. El-Sherif N. The figure-8 model of reentrant excitation in the    canine postinfarction heart. In Zipes D P, Jalife J, eds: Cardiac    Electrophysiology: From Cell to Bedside. W B Saunders, Philadelphia,    1995, pp 363-378.-   6. Ciaccio E J, Tosti A C, Scheinman M M. Relationship between sinus    rhythm activation and the reentrant ventricular tachycardia isthmus.    Circulation. 2001; 104: 613-619.-   7. Ciaccio E J, Costeas C A, Coromilas J, et al. Static relationship    of cycle-length to reentrant circuit geometry. Circulation, 2001;    104:1946-1951.-   8. Ciaccio E J. Dynamic relationship of cycle length to reentrant    circuit geometry and to the slow conduction zone during ventricular    tachycardia. Circulation 2001; 103:1017-1024.-   9. Ciaccio E J. Localization of the slow conduction zone during    reentrant ventricular tachycardia. Circulation 2000; 102: 464-469.-   10. Dillon S M, Allessie M A, Ursell P C, et al. Influences of    anisotropic tissue structure on reentrant circuits in the epicardial    border zone of subacute canine infarcts. Circulation Research 1988;    63:182-206.-   11. Peters N S, Coromilas J, Severs N J, et al. Disturbed connexin43    gap-junction distribution correlates with the location of reentrant    circuits in the epicardial border zone of healing canine infarcts    that cause ventricular tachycardia. Circulation 1997; 95:988-996.-   12. Spach M S, Miller W T III, Dolber P C, et al. The functional    role of structural complexities in the propagation of depolarization    in the atrium of the dog. Circulation Research 1982; 50:175-191.-   13. Kogan B Y, Karplus W J, Billett B S, et al: Excitation wave    propagation within narrow pathways: Geometric configurations    facilitating unidirectional block and reentry. Physica D 1992;    59:275-296.-   14. Rohr S, Salzberg B M. Characterization of impulse propagation at    the microscopic level across geometrically defined expansions of    excitable tissue: multiple site optical recording transmembrane    voltage (MSORTV) in patterned growth heart cell cultures. J Gen    Physiol 1994; 104:287-309.-   15. Peters N S, Coromilas J, Hanna M S, et al. Characteristics of    the temporal and spatial excitable gap in anisotropic reentrant    circuits causing sustained ventricular tachycardia. Circ Res 1998;    82:279-293.-   16. Sato M, Sakurai M, Yotsukura A, et al. The efficacy of    radiofrequency catheter ablation for the treatment of ventricular    tachycardia associated with cardiomyopathy. Jpn Circ J. 1997;    61:55-63.-   17. Chinushi M, Aizawa Y, Miyajima S, et al. Proarrhythmic effects    of antiarrhythmic drugs assessed by electrophysiologic study in    recurrent sustained ventricular tachycardia. Jpn Circ J 1991;    55:133-141.    Third Series of Experiments

Knowledge of the pathway common to both wave fronts in figure-8reentrant circuits (i.e., the isthmus) is of importance for catheterablation to stop reentrant ventricular tachycardia. It was hypothesizedthat quantitative measures of reentry isthmus geometry were interrelatedand could be correlated with tachycardia cycle length.

A canine infarct model of reentrant ventricular tachycardia in theepicardial border zone with a figure-8 pattern of conduction was usedfor initial analysis (experiments in 20 canine hearts with monomorphicreentry). Sinus-rhythm and reentry activation maps were constructed, andquantitative (skeletonized) geometric parameters of the isthmus andborder zone were measured from the maps. Regression equations were usedto determine significant correlation relationships between skeletonizedvariables, which can be described as follows. Tachycardia cycle length,measured from the ECG R-R interval, increases with increasing isthmuslength, width, narrowest width, angle with respect to muscle fibers, andcircuit path length determined by use of sinus-rhythm measurements.After this procedure, in 5 test-set experiments, tachycardia cyclelength measured from the R-R interval, in combination with regressioncoefficients calculated from initial experiments, correctly predictedisthmus geometry (mean estimated/actual isthmus overlap 70.5%). Also,the circuit path length determined with sinus-rhythm measurementscorrectly estimated the tachycardia cycle length (mean error 6.2±2.5ms). Accordingly, it is shown that correlation relationships derivedfrom measurements using reentry and sinus-rhythm activation maps areuseful to assess isthmus geometry on the basis of tachycardia cyclelength. Such estimates may improve catheter ablation site targetingduring clinical electrophysiological study.

For treatment of reentrant ventricular tachycardia, catheter ablation isoften the method of choice because it does not involve surgery, there islow morbidity, and it is frequently effective at stopping tachycardiaand preventing recurrence. [1] The target site for ablation of reentryis the central common pathway, or isthmus, which is a protected regionthrough which the propagating wave front is constrained by arcs ofconduction block. [2,3] Some reentrant circuits are difficult to ablateduring clinical electrophysiological study because it is problematic toascertain the precise location and/or geometric characteristics of theisthmus. [1-3] Concealed entrainment procedures are an important methodto pinpoint the location of the standard ablation catheter tip withrespect to the isthmus entrance or exit; however, isthmus shape is notdiscerned. [4-6] Therefore, the best ablation lesion (length andorientation) to block the impulse as it traverses the isthmus cannotpresently be determined by a standard mapping catheter except by eithertrial and error or use of extensive, time-consuming mapping procedures.[7] Currently, even when an ablation lesion terminates reentry, it doesnot always preclude reinitiation of the same reentry morphology orestablishment of a new reentry morphology, [8] suggesting that suchlesions may be off center with respect to the optimal target site.

Improved knowledge of circuit geometry before catheter ablation canpotentially increase the success rate for terminating reentrantventricular tachycardia without recurrence of the same or anothermorphology, because ablation site targeting can be achieved in part onthe basis of assessment of isthmus shape. This study tested thehypothesis that ventricular tachycardia cycle length can be correlatedwith reentrant circuit geometry and with sinus-rhythm activationcharacteristics in a canine model. If tachycardia cycle length, inconjunction with measurements made during sinus rhythm, could be used toestimate geometric properties of the reentrant circuit during clinicalelectrophysiological study, it would potentially enhance the speed andaccuracy of ablation therapy even under circumstances of hemodynamicintolerance in which extensive mapping information is unobtainablebefore tachycardia termination.

A. Methods

Myocardial infarcts were created within the subepicardium of in situcanine hearts by ligation of the left anterior descending coronaryartery (LAD). [9] Electrophysiological study was done 4 to 5 days afterLAD ligation. Dogs were anesthetized with sodium pentobarbital, thechest was opened and positive-pressure ventilation applied, andrecordings were made from the epicardial border zone of the anteriorleft ventricle with a 196- to 312-channel array. The distance betweenpoles of each bipolar electrode was 3 mm, and the spacing betweenbipolar electrodes was 4 to 5 mm. A fixed signal gain of ×100 was usedfor first-stage amplification, and a ×1 to ×128 gain determinedautomatically by computer software was used for second-stageamplification, so that the final signal peak-to-peak level was between 2and 8 V. The signal pass band was 2 to 500 Hz. For 20 training-setcanine heart experiments, data were acquired during sinus rhythm,pacing, and monomorphic reentrant ventricular tachycardia with figure-8conduction pattern[10] that was induced by programmed electricalstimulation (10 Spacing cycles followed by a premature stimulus).Activation maps were made by automatically marking activation times ofelectrogram signals by slope and peak criteria and printing the timesfor all sites on a computerized map grid. [9] Arcs of block separatedsites in which activation differed by >40 ms and where wave fronts onopposite sides of the arcs moved in different directions in the maps.[9]

FIG. 17A shows, for a selected canine heart experiment, the reentryactivation map for the first cycle of tachycardia after onset in whichthe cycle length had stabilized, which was determined as describedpreviously for this model. [11] The reentry isthmus is bounded by 2 arcsof block (locations are shown as superimposed thick curved black lines).Activation proceeds through the isthmus toward the apical margin of theborder zone and then bifurcates and turns upward in the map toward theLAD basal border. From the reentry map computerized grid, severalgeometric measurements were made, which are said to be skeletonized[12]because they reduce the complexity of the 2D shape into a line drawing(FIG. 17B): (1) length (L): end point to end point length of an arc ofblock bounding the isthmus, averaged for the 2 arcs (L₁+L₂)/2; (2) width(W): average distance across the arcs of block at the end points(W₁+W₂)/2; (3) narrowest width (W_(N)): minimum distance across theisthmus and its location; (4) angle (A): unsigned average orientation ofL₁ and L₂ with respect to muscle fiber direction; (5) spurs (S): lengthsand locations of any short arcs of block branching from the isthmus; (6)center location of the isthmus (XY): midpoint of vector A; and (7)relative locations at which isochrones insert into the isthmus arcs ofblock (FIG. 17A).

Muscle fiber direction was determined from an activation map constructedfrom center pacing during sinus rhythm (FIG. 17C). Fiber angle wasconsidered to be in parallel with the direction of the most rapidelectrical conduction away from the paced zone, which is toward the LADand toward the apex in the map. Separate maps were constructed ofindividual skeletonized reentry parameters for each experiment at theonset of stable tachycardia cycle length and for the mean skeletonizedparameters from all experiments.

Sinus-rhythm data without pacing were then used to measure a parametercalled the electrogram duration. This parameter is defined as thatcontiguous series of electrogram deflections, with no isoelectricsegment of >5 ms duration, encompassing the time of local activation atthe recording site during 1 cardiac cycle. [13] The starting, and endingpoints, respectively, were considered to be the beginning and endingtimes at which contiguous electrogram deflections rose above theisoelectric level to an amplitude >10% of the maximum electrogram peak.Electrogram duration was mapped by use of the same automated,computerized electrode grid that was used for activation mapping. Anexample is shown in FIG. 17D, in which reentry arcs of block locationsare superimposed as thick curved lines. The shortest pathway aroundeither of the superimposed arcs of block for which electrogram durationwas <40 ms (called the circuit path length, or PL, which is denoted as adotted line in FIG. 17D) was computed methodically as follows. A minimumnumber of piecewise linear segments were positioned on the map grid atlocations around the arc of block such that the entire pathway wasconstrained to areas of short (<40-ms) electrogram duration. Path lengthwas then equal to the summed lengths of the piecewise linear segments.

The above mapping and skeletonization procedure was initially done byone person (observer 1). Best-subsets linear regression (SigmaStat V2.0,Jandel Scientific) was used to describe significant relationships(P<0.001) between the skeletonized parameters and the tachycardia cyclelength, which was measured from the R-R interval of the ECG. To assessmeasurement reproducibility, another arbitrary cycle of sinus rhythm anda cycle of tachycardia near termination were mapped and skeletonized bythe same person (observer 1). Thereafter, a second person (observer 2)mapped, for skeletonization, the same cycles of sinus rhythm andventricular tachycardia as observer 1. The Pearson product momentcorrelation (SigmaStat V2.0, Jandel Scientific) was used to analyze theagreement in skeletonized parameters measured for different cardiaccycles by the same observer and also between the 2 observers.

The significant correlation coefficients (P<0.001) determined from the20 training-set canine heart experiments were used to assess 5 test-setcanine heart experiments. For each test-set experiment, the reentrycycle length measured from the ECG R-R interval, in conjunction with thelinear regression coefficients determined from the training-setexperiments, was used to provide an estimate of the isthmus geometry(shape and orientation). Because the estimate of skeletonized angle withrespect to muscle fiber orientation was unsigned, for simplicity it waschosen in the direction for best overlap with the actual reentry arcs ofblock determined from activation mapping. To quantify overlap, theisthmus centers were made coincident on the computerized grid, and as afirst approximation, the narrowest width was drawn at the center of theestimated isthmus. The center of the actual isthmus was taken as themean XY location of the 4 end points of the arcs of block, and thecenter of the skeletonized isthmus was taken as the midpoint of theangle vector. The area percent by which the skeletonized isthmusoverlapped the actual isthmus was then computed for each test set.

B. Results

FIGS. 18A-18T show maps of selected skeletonized isthmus parameters foreach experiment, from the measurements of observer 1, with the mapsordered according to cycle length. The reentry circuit of FIG. 17A-17Eis shown in FIG. 18I. Isthmuses with greatest cycle length tended to belarger in both length and width (FIG. 18A through 18L). In many of themaps, the wave front propagates through the reentry isthmus toward theLAD basal margin. There is no evident relationship of cycle length withXY location. The mean skeletonized circuit from the 20 training-setexperiments is shown in FIG. 19. Mean skeletonized isthmus length,width, and narrowest width were 20.3 mm, 18.4 mm, and 10.8 mm,respectively, and mean tachycardia cycle length was 198.8 ms. The meanisthmus angle was 23.4° to the left of vertical in the map,approximately in line with muscle fiber orientation at the mean XYisthmus location for all experiments. The isthmus is narrowed near itscenter, and slower conduction occurs there and at the pivot pointsaround the arcs of block. Conduction velocity is rapid at the isthmusexit and along the straightaway locations outside the isthmus.

FIG. 20 shows a table of significant correlation relationships betweenskeletonized variables at the onset of stable tachycardia cycle length.Tachycardia cycle length (CL) is highly correlated with the path length(PL) determined during sinus rhythm (Equation α). There is asecond-order relationship between skeletonized isthmus length and width(Equation 1), isthmus length and angle are correlated with cycle length(Equations 2 to 4), and narrowest width is correlated with width(Equation 5). The correlation in skeletonized parameters measured fordifferent cardiac cycles by the same observer, and also between the 2observers, was significant (P<0.02).

From the reentry cycle length measured by use of the R-R interval of theECG and the coefficients of Equations 1 and 3 to 5 in FIG. 20, isthmusgeometry was assessed for 5 test-set experiments, and the result isshown in FIGS. 21A-21E. In each experiment, the original arcs of blocklocations from the reentry activation maps are shown as black, and theestimated locations from skeletonized geometry coefficients are shown asgray. The actual and estimated arcs of block are more nearly coincidentwhen the actual arcs of block were approximately parallel (FIGS. 21Athrough C), because the skeletonization process did not account forrelative differences in orientation between the 2 arcs. There was a meanoverlap of 70.5% for the 5 test-set experiments. Equation ^(α)was thenused to estimate tachycardia cycle length from the path lengthdetermined from sinus-rhythm data in each test-set experiment, with goodagreement with the actual cycle length (mean difference betweenestimated/actual cycle length was 6.2±2.5 ms).

C. Discussion

1. Tachycardia Cycle Length and Skeletonized Parameters

The skeletonized length and angle in tandem were highly correlated withcycle length (FIG. 20, Equation 2), as might be anticipated becauseisthmus length contributes to the circuit path length, whereas isthmusangle contributes to conduction velocity around the path; path lengthand conduction velocity are the determinants of tachycardia cyclelength. As skeletonized isthmus length increased, tachycardia cyclelength tended to increase (Equation 4). Hence, isthmus length is likelyto be constrained by the possible range in cycle lengths. The length ofthe isthmus cannot increase such that it prolongs the tachycardia cyclelength beyond the time that a sinus escape beat would occur. Also,isthmus length cannot decrease below a level at which it would result inarrival of the activating wave front at a particular portion of thecircuit during the relative refractory period (causing slowedconduction) and/or during the absolute refractory period (causingblock). As conduction velocity diminished with increasing angle of theisthmus away from muscle fibers, tachycardia cycle length also increased(Equation 3), in agreement with experimental and theoretical studies ofthe anisotropic relationship between these variables. [14,15] In thepresent study, the single cycle (static case) tachycardia cycle lengthnear the onset of stability and also near tachycardia termination werefound separately over many experiments to be directly proportional tothe isthmus length during those cycles. During a particular reentryexperiment, however, it was shown elsewhere in this same animal modelthat over many cardiac cycles (dynamic case), there is a reverserelationship between tachycardia cycle length and isthmus length becauseof changes in conduction velocity of the activation wave front as ittraverses the slow conduction zone that occur over the course oftachycardia (i.e., the isthmus lengthens when cycle length decreases andshortens when cycle length increases). [11]

By definition, the sinus-rhythm electrogram duration parameter was ameasurement of the electrical activity occurring in proximity to therecording electrode and did not include isolated late potentials (seeMethods section); hence, this measurement would be expected to beinfluenced by factors affecting local activity only, such as wave-frontconduction velocity near the recording site. At tachycardia onset forthe experiment whose activation map is shown in FIG. 17A, relativelyrapid conduction occurred as the propagating wave front coursed aroundthe left block line (FIG. 17A), and sinus-rhythm electrogram durationthere was relatively short (path denoted PL in FIG. 17D), whereasrelatively slow conduction occurred around the right block line,particularly along the lateral edge of the map grid (FIG. 17A), andsinus-rhythm electrogram duration there was relatively long (FIG. 17D).The left wave front crossed the isthmus entrance ≈20 ms before the rightwave front; hence, the left loop along which the electrogram duration isrelatively short can be said to drive the reentry circuit and thereforethe tachycardia cycle length (CL). Therefore, heterogeneity of theborder zone substrate is probably reflected in the spatial variabilityof the electrogram duration maps (see FIG. 17D) and manifested asconduction velocity variations along the path. For all experiments,conduction velocity during reentry was observed to be rapid along tractsof short sinus-rhythm electrogram duration. If such tracts, and therapid wave fronts associated with them, extended far from the isthmustoward the periphery of the border zone, then wave-front componentscrossing areas of longer electrogram duration, although moving moreslowly, could potentially arrive at the isthmus entrance more rapidly,thereby skewing the linearity of the CL-PL relationship (FIG. 20,Equation α).

2. Interrelationships Between Skeletonized Parameters

FIG. 19 shows the mean skeletonized parameters; the mean isthmus fromall experiments approximately aligns with muscle fiber orientation atthe mean XY location. This phenomenon may be related to the setup oftachycardia: during premature stimulation leading to reentry onset, aunidirectional arc of block forms, and the wave front bifurcates andproceeds around it. The same wave front coalesces on the other side ofthe unidirectional arc and breaks through to reenter the previouslyexcited tissue if there is sufficient delay for recovery ofexcitability.

Wave front traversal around the arc will be slowest (hence, the greatestchance for delay necessary for reentry induction) if it propagatesperpendicular to muscle fiber orientation. To meet this condition, theisthmus long axis, which generally aligns in parallel with the directionof reentry breakthrough during the premature cycle, [13] would mostcommonly reside in parallel with muscle fiber orientation, as wasobserved. Also in FIG. 19, the narrowest portion of the isthmus iscoincident with the zone of slow conduction. This may be the result ofan aperture effect in which insufficient current is available for normalactivation as the wave front proceeds out of the aperture and into anarea of distal expansion. [16]

Correlation between the skeletonized variables can potentially provideinformation concerning the range of possible shapes that the reentryisthmus may possess. The strong second-order relationship betweenskeletonized isthmus length and width (FIG. 20, Equation 1) can bestated as follows. When the reentry isthmus is narrow in this caninemodel, it tends to be either long or short in length, and when it iswide, it tends to be of intermediate length. An isthmus having largedimensions of both length and width may be uncommon, because the pathlength could prolong tachycardia cycle length to the extent that asinus-rhythm escape beat would capture conduction of the heart. Were theisthmus very short and wide, which is also uncommon in this model, theactivating wave front would no longer be constrained to enter theisthmus at an angle approximately in parallel with the bounding arcs ofblock. One end of the wave front, for example, might cross the isthmusexit while the other edge lagged behind at the isthmus entrance. Thiscould act to destabilize the excitable gap, [17] which depends in parton synchronicity of conduction along symmetrical portions of the circuitto be maintained, and therefore act to destabilize the functional arcsof block that bound the reentry isthmus. The relationship betweenisthmus width and narrowest width (Equation 5) suggests that block linesbounding the isthmus are often tapered inward by a constant proportion,regardless of the magnitude of isthmus width.

3. Clinical Implications of Skeletonized Geometry

When a standard ablation catheter is used during clinicalelectrophysiological study, most methods for targeting sites rely onmeasurement of border-zone parameters that can be related to reentryisthmus geometry. [1-3] For example, concealed entrainment methods arebased on timing considerations between electrical activation at the pacesite and features of the ECG signal, [1,3-6] but the success rate isvaried,. Depending on isthmus width, if the site location were withinthe isthmus but off center with respect to the midline, the ablationlesion could actually serve to reinforce any arc of block bounding theisthmus that is adjacent to the ablation electrode. It could alsopotentially constrict the isthmus without complete interruption of thecircuit. The effect of any such isthmus stricture caused by an ablationlesion might be to decelerate conduction velocity and prolong cyclelength, as has been observed during a clinical study, [18] becausecurrent infused to areas distal to the stricture in the circuit isdiminished. [16] If for clinical study, isthmus shape could be estimatedby use of skeletonized regression coefficients in conjunction with ameasurement of tachycardia cycle length from the ECG R-R interval, itwould be of potential benefit for targeting ablation sites to know apriori the characteristics of the isthmus that are of importance fordetermining the best lesion length and orientation. Ideally, measurementof tachycardia cycle length from the patient's ECG would be done beforeelectrophysiological study, recorded, for example, with a Holtermonitor, so that ablation therapy could be planned accordingly. Theskeletonized isthmus angle estimate described here is unsigned; hence,there are 2 possible orientations with respect to muscle fiber direction(+/−). For the measurement to be useful, therefore, it would benecessary during clinical therapy to have some knowledge of thepropagation direction through the isthmus, for example, by considerationof proximal and distal activation times when the catheter tip is locatedin proximity to the reentry circuit.

The reentry circuit path length, which was measured by use of thesinus-rhythm electrogram duration parameter, was also found to be highlycorrelated with tachycardia cycle length measured from the ECG R-Rinterval. On the basis of the correlation coefficient derived from thismeasurement and the path length determined from sinus-rhythm electrogramduration maps, tachycardia cycle length was correctly estimated (meanerror 6.2±2.5 ms). Estimation of tachycardia cycle length beforetachycardia induction during clinical study, using isthmus boundariesdetermined from sinus rhythm measurements, [13] is potentially useful togauge toleration of the tachycardia by the patient and the effect of anyarrhythmic drug to be administered during tachycardia, both of which arein part rate-dependent. [14]

Isthmus arcs of block were localized by spline interpolation to 0.1 mm,which was beyond the 4- to 5-mm resolution of the multielectrode arraybut consistent from one activation map to the next. Any inaccuracy inplacement of the arcs of block may serve to decrease the significance ofcorrelation between variables; higher electrode spatial resolution mayreveal other geometric variables with significant correlation. Thesimple measurements used to gauge isthmus geometry are not indicative ofsubtle features of the circuit. For improved representation, moresophisticated geometric measurements might be useful; however, thecomplexity of analysis would increase. At present, it is unknown how theproperties of functional circuits for the canine model described heremight apply to ventricular tachycardia circuits in human patients, inwhom the isthmus may more frequently be bounded by anatomic arcs ofblock. [1] Use of an anatomic model of reentry in canine hearts mightbetter serve to describe some reentry episodes in humans with parametersof skeletonized geometry. Skeletonized geometry methods may also beuseful to assess the effect of isthmus orientation with respect tomuscle fibers on the action of antiarrhythmic drugs that preferentiallyimpede conduction in either the longitudinal or transverse direction.

D. References For Third Series of Experiements

-   1. Stevenson W G, Friedman P L, Kocovic D, et al. Radiofrequency    catheter ablation of ventricular tachycardia after myocardial    infarction. Circulation. 1998; 98: 308-314.-   2. Krishnan S C, Josephson M E. Mapping techniques and catheter    ablation of ventricular tachycardia due to coronary artery disease.    Arch Mal Coeur Vaiss. 1998; 91: 21-26.-   3. Stevenson W G, Khan H, Sager P, et al. Identification of reentry    circuit sites during catheter mapping and radiofrequency ablation of    ventricular tachycardia late after myocardial infarction.    Circulation. 1993; 88: 1647-1670.-   4. Bogun F, Knight B, Goyal R, et al. Clinical value of the    postpacing interval for mapping of ventricular tachycardia in    patients with prior myocardial infarction. J Cardiovasc    Electrophysiol. 1999; 10: 43-51.-   5. Hadjis T A, Harada T, Stevenson W G, et al. Effect of recording    site on postpacing interval measurement during catheter mapping and    entrainment of postinfarction ventricular tachycardia. J Cardiovasc    Electrophysiol. 1997; 8: 398-404.-   6. Bogun F, Bahu M, Knight B P, et al. Comparison of effective and    ineffective target sites that demonstrate concealed entrainment in    patients with coronary artery disease undergoing radiofrequency    ablation of ventricular tachycardia. Circulation. 1997; 95: 183-190.-   7. Stevenson W G, Sager P T, Natterson P D, et al. Relation of    pace-mapping QRS configuration and conduction delay to ventricular    tachycardia reentry circuits in human infarct scars. J Am Coll    Cardiol. 1995; 26: 481-488.-   8. Aizawa Y, Chinushi M, Naitoh N, et al. Catheter ablation of    ventricular tachycardia with radiofrequency currents, with special    reference to the termination and minor morphologic change of    reinduced ventricular tachycardia. Am J Cardiol. 1995; 76: 574-579.-   9. Dillon S M, Allessie M A, Ursell P C, et al. Influences of    anisotropic tissue structure on reentrant circuits in epicardial    border zone of subacute canine infarcts. Circ Res. 1988; 63:    182-206.-   10. El-Sherif N. The figure-8 model of reentrant excitation in the    postinfarction canine heart.In: Zipes D P, Jalife J, eds. Cardiac    Electrophysiology: From Cell to Bedside. Philadelphia, Pa.: W B    Saunders Co; 1995: 363-378.-   11. Ciaccio E J. Dynamic relationship of cycle length to reentrant    circuit geometry and to the slow conduction zone during ventricular    tachycardia. Circulation. 2001; 103: 1017-1024.-   12. Russ J C. The Image Processing Handbook. Boca Raton, Fla.: CRC    Press; 1995: 456-462.-   13. Ciaccio E J, Tosti A C, Scheinman M M. Relationship between    sinus rhythm activation and the reentrant ventricular tachycardia    isthmus. Circulation. 2001; 104: 613-619.-   14. Wit A L, Janse M J. Basic mechanisms of arrhythmias.In: Wit A L,    Janse M J, eds. The Ventricular Arrhythmias of Ischemia and    Infarction. New York, N.Y.: Futura; 1993: 1-160.-   15. Gardner P I, Ursell P C, Fenoglio J J Jr, et al.    Electrophysiologic and anatomic basis for fractionated electrograms    recorded from healed myocardial infarcts. Circulation. 1985; 72:    596-611.-   16. Kogan B Y, Karplus W J, Billett B S, et al. Excitation wave    propagation within narrow pathways: geometric configurations    facilitating unidirectional block and reentry. Physica D. 1992; 59:    275-296.-   17. Peters N S, Coromilas J, Hanna M S, et al. Characteristics of    the temporal and spatial excitable gap in anisotropic reentrant    circuits causing sustained ventricular tachycardia. Circ Res. 1998;    82: 279-293.-   18. Ellison K E, Friedman P L, Ganz L I, et al. Entrainment mapping    and radiofrequency catheter ablation of ventricular tachycardia in    right ventricular dysplasia. J Am Coll Cardiol. 1998; 32: 724-728.    Fourth Series of Experiments

It was hypothesized that quantitative sinus-rhythm electrogrammeasurements could be used to predict conduction events resulting frompremature stimulation, and reentrant ventricular tachycardiainducibility.

Sinus rhythm activation and electrogram duration maps were constructedfrom bipolar electrograms acquired at 196-312 sites in the epicardialborder zone of 43 canine hearts (25 with reentrant ventriculartachycardia inducible by premature stimulation and 18 lackinginducibility). From these maps, lines of electrical discontinuity whereblock would occur during premature excitation were estimated. The meanerror in distance between the estimated and actual block line ofpremature excitation was 0.97 cm. Based on the quantitativecharacteristics of the activation and electrogram duration maps and thelongest block line forming during premature excitation, whether or notreentry would occur was predictable (sensitivity 94.7%, specificity79.6%). In reentry experiments, the breakthrough. point location alongthe unidirectional arc of block which initiated reentry was alsopredictable (mean error, 0.79 cm). Accordingly, it would appear thatsinus-rhythm measurements are useful to predict conduction eventsresulting from premature stimulation, and reentry inducibility.

The precise relationship between the pattern of electrical activationthat occurs during sinus rhythm versus the pattern of activation duringpremature excitation in the infarct border zone heretofore has beenincompletely understood¹. Properties of nonuniform anisotropicconduction can account for some of the observed phenomena that lead toinduction of reentrant ventricular tachycardia following prematurestimulation, for example, the tendency of the long-axis of the centralcommon pathway, or isthmus, of figure-8 reentrant circuits to oftenalign approximately in parallel to muscle fibers¹. However, in a canineinfarct model study in which reentry in the epicardial border zone wasinduced by programmed stimulation, the long-axis of the isthmus was notalways aligned with muscle fiber orientation and was actually orientedtransversely in approximately 15% of experiments². It is likely,therefore, that other factors are of importance besides anisotropy ingoverning the formation of functional arcs of conduction block at theonset of reentrant ventricular tachycardia.

Recent work suggests that electrical discontinuities present in theinfarct border zone may be of great importance in determining thepattern of activation during reentry. For example, it was determined ina canine reentry model study that the location where the isthmus of thereentrant circuit formed was uniquely marked by disruption of the gapjunctional distribution that extended the full thickness of the borderzone layer³. In the study it was proposed that the arcs of conductionblock bounding the reentry isthmus coincide with edges of the area offull-thickness gap-junctional disruption, at segments alignedapproximately in parallel with muscle fibers³. The combined effect of anelectrical discontinuity in gap-junctional properties and transverseorientation of any oncoming wave-front at these locations wasanticipated to block electrical conduction during reentry³.

In another study using the same canine infarct model it was shown thatareas of the border zone having rapid conduction during reentrantventricular tachycardia tend to have a short sinus rhythm electrogramduration⁴, which is therefore likely to be reflective of the degree ofabnormality of the substrate. Furthermore, boundaries between areas withlarge differences in electrogram duration during sinus rhythm, wherediscontinuities in electrical properties were anticipated to occur, werecoincident with the positions of arcs of functional conduction blockpresent during reentrant ventricular tachycardia⁴. Hence, areas of rapidactivation and areas of electrical discontinuity during sinus rhythm,which can be detected and localized by measurement of sinus rhythmelectrograms, are presumably important factors governing the setup,initiation, and localization of reentrant circuits in the infarct borderzone. It was hypothesized for the present study that areas of the borderzone with less abnormality, and areas of electrical discontinuity, asdetected and localized by sinus rhythm electrogram measurement, could beused to predict the electrical activation pattern during prematureexcitation, and reentry inducibility. As in previous studies, sinusrhythm electrograms were used for measurement because in these signalsit is relatively simple to quantify the interval of local activity andthe starting points of isoelectric intervals, compared with signalsobtained during ventricular pacing or ventricular tachycardia, asdescribed below.

A. Methods

The following procedures were used to extract the data during caninepostinfarction experiments and to measure characteristics of theactivation pattern in the infarct border zone during sinus rhythm,premature excitation, and ventricular tachycardia.

1. Data Collection and Mapping

A myocardial infarct was created by ligation of the left anteriordescending coronary artery (LAD) in situ in experiments in 43 caninehearts. Four to five days later, canines were anesthetized with sodiumpentobarbitol (30 mg/kg), the chest was opened and positive pressureventilation applied. A bipolar electrode multiarray was then suturedonto the anterior surface of the canine heart for recording andstimulation. Bipolar electrograms were recorded from 196-312 sites inthe epicardial border zone of the anterior left ventricle at an averagespatial resolution of 4-5 mm, and were amplified 100-1000× by a computersoftware auto-gaining procedure. The signal pass-band applied prior todigitization of the signals had high and low pass corner frequencies of2 Hz and 500 Hz respectively. Attempts to induce reentry were made inthese hearts by premature electrical stimulation⁵. Stimulatingelectrodes embedded in the recording multi-electrode arrays enabledpacing from constant locations at the LAD, lateral, base, and centerregion of the anterior epicardial surface. Programmed stimulationproceeded using ten S1 stimuli followed by a single S2 prematurestimulus. The premature coupling intervals were successively shortenedon subsequent stimulus trains until reentry was induced or blockoccurred. For consistency between experiments, the electrode multiarraywas placed on the heart with the same edge always positioned along theLAD margin. For simplicity, the region of the ventricle where recordingsites in the multiarray were located was considered to be coincident, toa first approximation, with the entire infarct border zone.

Twenty-five experiments in which long runs (>10 beats) of monomorphicreentrant ventricular tachycardia could be repetitively induced bypremature stimulation, and 18 experiments lacking reentry inducibility,were used retrospectively for the present study to investigate therelationship between sinus rhythm electrogram characteristics and theactivation pattern during premature excitation. These same data wereused previously to study the relationship between sinus rhythmelectrogram characteristics and the activation pattern during reentrantventricular tachycardia⁴. For simplicity, experiments in which onlyshort runs (<10 beats) of tachycardia were inducible, which would bemore complex to characterize quantitatively, were not included in thepresent study.

Activation maps of sinus rhythm, pacing, and reentry (when it occurred)were made by automatically marking activation times of electrogramsignals at the point of sharpest slope along the largest peakdeflection, and printing the times for all sites on a computerized mapgrid⁵. Upon visual inspection of the resulting activation map, wherecontext with respect to neighboring recording sites suggested that theactivation time at a particular site lacked continuity, the electrogramwas re-marked at the sharpest slope of any electrogram deflection, whenpresent, that more closely coincided with the activation times ofneighboring sites. This set of rules was applied to ensure consistencyin the activation marking procedure. The locations of arcs of conductionblock were drawn on the map grid between sites in which activationdiffered by more than 40 ms and where wavefronts on opposite sides ofthe arcs moved in different directions according to the maps⁵. Arcs weredrawn using a spline interpolation function to 0.1 mm precision, whichwas beyond the resolution of the electrode multiarray, but consistentfrom one activation map to the next. Using the same computerizedelectrode grids that were used for activation mapping, sinus rhythmelectrogram duration maps (i.e., activation duration) were thenconstructed as described previously⁴. The sinus rhythm electrogramduration was measured for each recorded signal during a single arbitrarycardiac cycle at the beginning of the experiment prior to any pacing ofthe heart. It is defined as the time interval from beginning to end ofthe contiguous series of electrogram deflections that includes the timeof local activation⁴. Contiguous deflections are those in which there isno isoelectric segment of more than 5 ms in length between successivedeflections. The electrogram duration was used as a distinct measure ofthe electrical activity in the border zone.

2. Localization of Lines of Electrical Discontinuity

From the sinus rhythm activation maps, the location and shape of linesof electrical discontinuity where arcs of conduction block would beexpected to form during premature excitation were predicted as follows.Points where the difference in activation time between adjacent sites(vertical, horizontal or diagonal directions) was greater than or equalto 10 ms were delimited on the computerized mapping grid as solidcircles. The 10 ms threshold was selected based on the observation madeduring initial mapping procedures that long, continuous arcs ofconduction block forming during premature excitation tended to occuralong areas with differences in sinus rhythm activation time on theorder of 10 ms between adjacent sites. Since the precision of activationmarking in our studies is ˜1-2 milliseconds⁵, the built-in redundancy(i.e., measurement of the difference at all adjacent sites in thevertical, horizontal or diagonal directions) helped ensure detection ofpertinent areas. Where the resulting set of points were less than 1 cmapart on the grid, they were considered to be contiguous, and splineinterpolation was used to form a curved line from the points, asdescribed elsewhere². This curved line was used as an estimate of thelocation of the longest (primary) arc of conduction block expected toform during premature excitation. For simplicity, statistics were onlycomputed for the longest arc of conduction block expected to form duringpremature excitation.

Once the estimated location of the longest block line that was expectedto form during premature excitation was established, the followingparameters were quantified using the computerized electrode grid formeasurements. The actual locations of arcs of conduction block formingduring premature excitation were determined from activation maps (actualarcs of block separated by less than 1 cm were considered contiguous formeasurement purposes). The longest actual versus estimated arc of blockof premature excitation were then compared by computing the surface areaenclosed by their outer boundaries, and dividing by the actual arclength to normalize the measurement (see FIG. 22F: surface area betweenarcs is denoted by crosshatched region). The symmetry of the longestactual arc of conduction block to form during premature excitation, withrespect to stimulus site position, was also determined mathematically.The distances d1 and d2 from the stimulus site to either endpoint of theactual block line were measured as shown in FIG. 22F, and symmetry wasthen computed as:Symmetry={[(d1+d2)−(d1−d2)]/(d1+d2)}*100%

From the above equation, if d1=d2, the ends of the arc of block would beperfectly symmetric with respect to stimulus site position i.e.,symmetry would be 100%. The symmetry will be less than 100% and positivewhen d1>d2 and negative when d2>d1. The absolute value of symmetry foreach experiment was then used to compute the mean symmetry for the 25reentry experiments. Also, the location along the predicted prematurearc of conduction block where electrogram duration on either side hadthe shortest mean value was estimated to be the breakthrough point thatwould result in initiation of reentry. It was hypothesized for thismeasurement that at the point of lowest mean electrogram duration acrossthe arc, the characteristics of electrical conduction would be closestto normal myocardial tissue, and therefore less subject to conductionblock compared with other areas where conduction was anticipated to bemore abnormal. For all reentry experiments, the XY (Euclidean) distancebetween actual and estimated breakthrough points on the computerizedgrid was then tabulated. For these measurements, the standard error wascalculated to show the variation from the mean.

Several additional measurements were made to determine if reentryinducibility could be predicted based on the activation characteristicsof premature excitation. Mean parameters of sinus rhythm activityassociated with the estimated line of block, the breakthrough point, andthe entire border zone were determined for each experiment as describedin FIG. 25, and the measurements were then pooled from all experimentsfor statistical purposes. Scatter-plots were constructed using theparameters described in FIG. 25, and optimal linear thresholds along oneand two dimensions were calculated using a linear discriminant functionto predict whether or not reentry would be inducible. Scatter plots withpredictive accuracy of greater than 80% are given in the Resultssection. The sensitivity (proportion of experiments with reentryinducibility that were correctly identified) and specificity (proportionof experiments lacking inducible reentry that were correctly identified)were also computed. Significant linear correlation between parameters(p<0.001) was then determined using a commercial computer program(SigmaStat, Jandel Scientific).

B. Results

FIGS. 22A-22I show electrogram maps for an experiment in which reentrywas inducible from the basal margin of the grid. In this experiment, thesinus rhythm cycle length was 414 ms, and ventricular tachycardia with acycle length of 176 ms was repetitively inducible by pacing the heartusing ten S1 stimuli having a coupling interval of 300 ms, followed by asingle premature stimulus 145 ms later. The sinus rhythm activation mapis shown in FIG. 22A. The locations between adjacent sites where theactivation time difference is greater than or equal to 10 ms aredelimited by solid circles superimposed on the computerized mappinggrid. Based on the positions of the points, curved lines were drawn byspline interpolation which were the predicted locations of conductionblock during premature excitation (blue lines, FIG. 22A). The sinusrhythm electrogram duration map for the cycle of FIG. 22A is shown inFIG. 22B, with the grayscale at top denoting the relationship betweengray level and the duration of the electrogram in milliseconds. Theestimated breakthrough point, located at the area with shortestelectrogram duration along the longest block line anticipated to occurduring premature excitation, is denoted by the center of the blue, arrowsuperimposed on the map of FIG. 22B. Smaller differences in activationtime tended to occur across the estimated breakthrough point whereelectrogram duration was shortest (FIGS. 22A and 22B). When paced fromthe center of the epicardial border zone at a coupling interval of 350ms (activation map of FIG. 22C), conduction was most rapid in thedirection denoted by the arrows. Based on anisotropic considerations inwhich the activation wave-front proceeds most rapidly in parallel withthe long-axis of normal myocardial cells¹, the arrows thereforeapproximate muscle fiber orientation in the border zone (i.e., coursingfrom LAD to APEX). Since the multielectrode grid was positioned with thesame side overlapping the left anterior descending coronary artery ofthe heart in all experiments (see Methods section), muscle fiberorientation was approximately the same for all maps constructed for thisstudy.

The effect of rapid programmed electrical stimulation was then assessed.During S1 pacing from the base (FIG. 22D), the longest estimated andactual arcs of block partially coincide. During premature excitationfrom the base (FIG. 22E) the longest estimated and actual arcs ofconduction block mostly overlap, and the estimated versus actualbreakthrough locations for initiation of reentry were also in closecorrespondence (center of blue and black arrows, respectively).Following-premature stimulation, conduction proceeds rapidly from thestimulus site at the base to quickly impinge upon the line ofdiscontinuity as a cohesive, approximately linear wave-front. Thedirection of the oncoming wave-front to the long line of electricaldiscontinuity is approximately normal, i.e., activation all along thetop, horizontal portion of the line occurs at approximately time 40 msand activation along most of the bottom, vertical portion of the lineoccurs at approximately time 80 ms (FIG. 22E). Illustrated in FIG. 22Fare some of the quantitative methods used for comparative calculations:the outer bounds of the surface area between estimated and actual arcsof block (crisscross region), the distance between estimated and actualbreakthrough points (short line between the solid circles, enlarged ininset), and the symmetry of the ends of the arcs of block to thestimulus site location (gray lines). It can be observed from the reentryactivation map that the block lines bounding the isthmus of thereentrant circuit partially align with those expected to form duringpremature excitation in this experiment (FIG. 22G). Following prematurestimulation from the lateral side (FIG. 22H), the short actual arc ofblock which formed adjacent to the stimulus site approximatelyoverlapped a short estimated block-line from FIG. 22A, shown in blue,and slow conduction occurred at the location of the other shortestimated block-line (note 20-40 ms isochrones which are bunched on themap of FIG. 22H near the stimulus site). Following premature stimulationfrom the center, the impulse was interrupted in coincidence with a largesegment of the longest estimated block-line of premature excitation(FIG. 22I). However near the basal margin, arrival of the activationwave-front was delayed, resulting in coalescence of individualwave-fronts there rather than block of a single propagating wave-front.As in FIG. 22A-22I, in other experiments where secondary lines ofelectrical discontinuity were detected, block did not actually occurthere if the primary arc of block shielded the secondary arc from impactof the activating wave-front in the normal direction.

FIGS. 23A-23Y show the results of sinus rhythm electrogram measurementsfor the 25 experiments with inducible reentry. The estimated versusactual longest block-lines to form during a premature stimulation cyclewhich resulted in initiation of reentry are shown, respectively, by blueand black curved lines. The coupling interval of this prematurestimulation cycle ranged from 135 ms (FIG. 23Q) to 220 ms (FIG. 23E).During any given experiment., the coupling interval of prematurestimulation that resulted in reentry onset changed by no more than 10-20ms between episodes of induction, and reentry could only be induced bystimulation at the site location denoted by the red pacing symbol foreach of the experiments of FIGS. 23A-23Y. Premature excitation resultedin tachycardia when the stimulation site was located at the LAD marginin 13 experiments, at the basal margin in 6 experiments, at center in 5experiments, and at the lateral margin in 1 experiment. The LAD andbasal stimulus site locations appear in relatively close proximity inthe two-dimensional activation maps of FIGS. 23A-23Y. To distinguishthem, for maps constructed using the 196 electrode array (FIG. 23A-23J),examples of pacing locations at the basal and LAD margins are denoted inFIG. 23B and 23D respectively. For maps that were constructed using the312 electrode array (FIG. 23K-23Y), examples of pacing locations at thebasal and LAD margins are denoted in FIG. 23K and 23L, respectively. Forall reentry experiments, the site at which a premature stimulus resultedin reentry was in an area where sinus rhythm activation was rapid.

The estimated and actual breakthrough points (centers of blue and blackarrows, respectively) are also shown in FIGS. 23A-23Y. In each case thedifference in sinus rhythm activation time was relatively short at theestimated breakthrough point (not shown). The details for the experimentof FIG. 22 are depicted in FIG. 23F. In two experiments (FIGS. 23K and23L) two reentry morphologies were inducible via premature stimulationand the location of the second isthmus is shown in red color. In oneexperiment (FIG. 23Y), breakthrough occurred across two arcs of blockand dual isthmuses were present during the same reentry morphology. Inall of the figures, there is often a close correspondence between theestimated and actual arcs of conduction block and the breakthroughpoints. For each experiment, there tended to be a delay of ˜20-60 msbetween arrival of the wave-front on the opposite side of theunidirectional block line and onset of reentry, which suggests thatconduction velocity tended to slow dramatically at this point (˜0.1-0.2m/s). From the experiments of FIGS. 23A-23Y, the absolute mean degree ofsymmetry, from the location of the site at which a premature stimulusresulted in reentry, to the ends of the arcs of block generated by thatstimulus, was 82±3%. The mean difference in location between the longestestimated versus actual arc of block to form during premature excitationwas 0.97±0.49 cm, and the mean distance between the estimated and actualbreakthrough points was 0.79±0.19 cm. The longest estimated and actualarcs of conduction block had mean lengths of 6.53±0.51 cm and 6.14±0.53cm, respectively, for reentry experiments, and 2.21±0.34 cm and2.31±0.34 cm, respectively, for experiments in which reentry was notinducible. Therefore, in experiments with reentry inducibility, the meanlength of the long arc of block forming during premature excitation wasapproximately thrice that of experiments lacking inducibility. Forcomparative purposes, the arcs of conduction block forming duringreentry are also shown in FIGS. 23A-23Y, denoted as dashed gray lines,with a gray arrow indicating activation direction during the diastolicinterval of reentry.

Scatter-plots of the electrogram parameters described in FIG. 25 thatcould be used for classification, with an accuracy greater than 80%, ofthe 43 experiments into those with versus lacking reentry inducibility,are given in FIGS. 24A-24C. A plot of the mean difference in sinusrhythm activation time across the location of the estimated arc ofblock, versus the length of that arc, was useful to predict reentryinducibility with an accuracy of 95.3% (FIG. 24A, solid line). Thisscatter-plot also indicates that reentry induction was most likely tooccur when the estimated arc-length of premature excitation wasrelatively long (>3.5 cm, dotted line) and arc-length alone could beused to predict inducibility of reentry (accuracy: 86.0%). A plot ofmean difference in sinus rhythm activation versus electrogram durationthroughout the border zone also was predictive of reentry inducibility(accuracy: 81.4%, FIG. 24B). The difference in activation time from theproximal to distal sides of the actual breakthrough point, versus timefrom premature stimulus to arrival of the wavefront at the proximal sideof the actual breakthrough point, was useful to predict reentryinducibility with an accuracy of 88.4% (solid line in FIG. 24C).Furthermore, the difference in activation time from the proximal todistal sides of the actual breakthrough point with a threshold of 68 mswas also predictive of reentry (accuracy: 81.4%; dashed line). Using thetwo-dimensional linear discriminant functions shown in the three graphsof FIGS. 24A-24C, the mean sensitivity of these parameters forclassification of experiments into those in which reentry would beinducible versus those lacking reentry was 94.7% and the meanspecificity was 79.6%.

In this series of experiments there was no significant linearcorrelation of the electrogram parameters to the sinus rhythm cyclelength or to the premature stimulation coupling interval that resultedin reentry induction. Linear regression relationships that weresignificant (p<0.001) are given in FIG. 26 and can be stated as follows.When the mean site-to-site difference in sinus rhythm activation timethroughout the border zone is large, the length of the arc of conductionblock estimated to form during premature excitation tends to be long(Equation 1), and there will be a relatively large mean difference insinus rhythm activation time across the arc location (Equation 2). Whenthis arc of block is long, the time interval for the activationwave-front to propagate from the premature stimulation site to thebreakthrough point is prolonged (Equation 3), which in turn is relatedto an increased difference in activation time on opposing sides of thebreakthrough point during the premature excitation cycle (Equation 4). Along estimated arc of, conduction block, and a large difference inactivation time on opposing sides of the predicted breakthrough pointduring the premature excitation cycle, are highly predictive thatreentry will actually occur (FIGS. 24A and 24C). In summary, theequations of FIG. 26 state that induction of reentry is directly relatedto the status of the border zone during sinus rhythm, as can bedetermined by quantification of electrogram shape, and to the resultingpattern of activation during premature excitation. When there is a highdegree of electrical abnormality throughout the infarct border zone, asmeasured by large mean difference in sinus rhythm activation time fromsite to site, the probability is increased that block will occur along along continuous portion of this tissue when the infarct border zone isexcited prematurely. The resulting long arc of conduction block delaysthe arrival time of the activation wave-front to the opposite side ofthe arc. If this delay is sufficiently long so that there is recovery ofexcitability in the initially activated region, breakthrough across thearc of block will likely occur to initiate reentry.

C. Discussion

In this study it was shown that sinus rhythm measurements can be usefulto predict functional lines of conduction block that form duringpremature excitation. Furthermore, from these measurements it ispossible to predict whether or not reentry will occur and the locationof the breakthrough point in the case of inducible reentry. Thesefindings are now discussed in detail.

1. Detection of Electrical Discontinuity from Sinus-rhythm Measurement

In the two-dimensional canine model used for this study application,arcs of conduction block tend to be functional, i.e., their occurrencedepends on transient electrical properties including the time forrecovery of excitability during a particular activation cycle, thewave-front orientation, and the quantity of current available foractivation^(1,5). However, the actual locations where functional arcs ofblock form both during premature excitation and during reentry tend tobe constrained to localized regions of the infarct border zone in thecanine hearts⁵, and can also possess similar properties of constancy inpatients⁶, although the exact correlation between reentry in canine andhuman hearts is presently uncertain, due in part to differences ininfarct ages. In a previous study of the relationship between sinusrhythm activity and reentrant circuits in the canine heart, it was shownthat the location and orientation of the isthmus long-axis, and its exitposition, were identifiable as a unique area with a large and relativelyuniform gradient in sinus rhythm activation time⁴. Since a segment ofthe longest block-line forming during premature excitation tends toalign perpendicular to the exit of the reentrant circuit isthmus (seeFIGS. 22A-22I and 23A-23Y), that segment is in consonance with thelocation and direction where the aforementioned gradient of sinus rhythmactivation is large. Where the electrical discontinuity is large, amarkedly increased effective axial resistivity would be expected tooccur⁷. Areas with large effective axial resistivity are most vulnerableto conduction block when transient electrical properties satisfy certainconditions⁷. Hence, boundary lines separating points with largedifferences in sinus rhythm activation time are likely to be coincidentwith lines of electrical discontinuity where the magnitude of theeffective axial resistivity is large. This suggests that electrogrammeasurements can be used to detect areas of electrical discontinuity inthe border zone substrate, relating to the pattern of activation duringpremature excitation and reentrant ventricular tachycardia, which couldpotentially be very useful to characterize the state of the heart at theborder zone without the need for invasive histologic study.

2. Correlation of Electrical Discontinuities to Full-ThicknessGap-Junctional Disruption

The estimated locations of arcs of conduction block forming duringpremature excitation tended to be concave in shape with respect tostimulus site position, and in a few experiments formed an approximatelyclosed contour (FIG. 23C, 23D, 23N, 23S, 23X). These demarcations mayrepresent edges of the region of full-thickness gap-junctionaldissociation which have been shown to coincide with the boundaries ofthe isthmus of the reentrant circuit³. Along such edges, where themagnitude of electrical discontinuity is great (i.e., where there is anabrupt spatial transition) the magnitude of the effective axialresistivity is also large⁷. Hence, formation of any block-line thereduring premature excitation from a particular stimulus site positionwould be anticipated to be less susceptible to transient electricalproperties, and therefore highly reproducible during repetitiveepisodes, as was observed. However, whenever two lines of electricaldiscontinuity were in proximity, block of the activation wave-frontalong one line during the premature excitation cycle, followed bybifurcation of the wave-front and propagation around the arc, tended toprevent block from occurring at the secondary line of discontinuity.This was likely due to the combined effects of: 1. the delay in arrivalat the secondary location with a resulting increased time for recoveryof excitability there, along with 2. coalescence of distinct wave-frontsarriving there from several directions rather than arrival of a coherentoncoming wave-front in a direction normal to the discontinuity.

Although regions of full thickness gap junctional disruption tend tocoincide with the location where the isthmus of the reentrant circuitforms³, other canine studies provide evidence that the magnitude of thetransition across any and all lines of electrical discontinuity andtheir proximity are also important determinants of isthmus shape. Forexample, it has been observed elsewhere that during an experiment inwhich only short runs of monomorphic tachycardia were inducible, arcs ofconduction block bounding the isthmus of the reentry circuit shiftedfrom one discontinuity to the other, causing the isthmus to narrow, andresulting in termination of tachycardia within a few cardiac cycles⁴. Inanother canine infarct study of the dynamics of long runs of reentrantventricular tachycardia, short segments of the arcs of block boundingthe reentry isthmus were observed to undergo gradual shifts in locationfrom one cardiac cycle to the next⁸; at these segments any electricaldiscontinuity would be anticipated to be weaker in magnitude ornonexistent, so that minute changes in transient electrical propertiescould result in moderate changes in block line location.

3. Position of the Stimulus Site that Initiates Reentry

In FIG. 22A it can be observed that activation of the border zoneproceeds inward from all margins (LAD, base, apex, and lateral) but ismost rapid from the base. This may suggest that the underlying substrateat the rapid location was potentially less abnormal than other areas ofthe border zone. Since healthy epicardial tissue is less refractory topremature stimulation¹, a premature impulse originating from the basalmargin for the experiment of FIGS. 22A-22I would be expected to mostrapidly propagate inward at the infarct border zone as a large, cohesivewave-front, compared with stimulus sites positioned elsewhere in theborder zone, which is essentially what was observed (compare FIG. 22E toFIGS. 22H-22I). For reentry induction, it is essential that rapid andapproximately simultaneous arrival of the premature impulse at allpoints along one side of a long line of electrical discontinuity occur(i.e., the oncoming wave-front is propagating approximately normal tothe line) so that nearly simultaneous conduction block along the entireline will result. This event will then be followed by wave-frontbifurcation, with the distinct wave-fronts propagating around the blockline so formed. The tissues on the opposite-side of the block-line wouldthen activate, and if it were of sufficient length so that asatisfactory delay is introduced, breakthrough would be expected tooccur at a point where the effective axial resistivity is lowest⁷. Thus,low effective axial resistivity is probably associated with the shortmean sinus rhythm electrogram duration that was observed to occur oneither side of the breakthrough point leading to reentry. Induction ofreentry, therefore, would be anticipated when the premature stimulationsite is located within a region with relatively rapid impulseconduction, and positioned so as to be approximately equidistant(symmetric) with respect to the ends of the longest line of electricaldiscontinuity. The outcome in this case would be a relatively rapidarrival of the wave-front along all points on one side of thediscontinuity line. As expected, in the series of reentry experiments ofthis study the premature stimulation site location was coincident withan area of rapid sinus rhythm activation (e.g., FIGS. 22A-22I), andapproximately symmetric with respect to the ends of the longest line ofelectrical discontinuity (FIGS. 22A-22I and 23A-23Y). Elsewhere in theborder zone where propagation of the activation wave-front during sinusrhythm was slow and/or discontinuous, any premature impulse originatingfrom those regions propagated less rapidly and cohesively, so as topreclude a nearly synchronous arrival normal to any long line ofelectrical discontinuity. The result in this latter case was wave-fronttermination and sinus capture, as when pacing from the lateral andcenter regions of border zone for the experiment of FIGS. 22H-22I).

4. Combined Factors Leading to Reentry Induction

According to the results of this study, a relatively long, continuousunidirectional arc of conduction block must form as the result ofpremature stimulation for initiation of reentry. Following formation ofthe arc, the wave-front then bifurcates and proceeds around it,traveling more slowly: 1. in the direction transverse to musclefibers^(1,10), 2. across any highly fractionated regions where there isdispersal of cells and zigzag conduction¹⁰, 3. at lines of electricaldiscontinuity where the effective axial resistivity is high⁷, and 4.within the area where the isthmus of the reentrant circuit forms,because gap-junctional interconnections have been disrupted and tend toconduct slowly when excited prematurely³. Increased magnitude of any ofthese factors acts to impede conduction and therefore to delay thearrival of the wave-front on the trailing side of the unidirectional arcat the point where it will potentially reenter the previously excitedarea. If the delay in its arrival is insufficient for recovery ofexcitability on the leading side of the unidirectional arc, reentry willnot occur. Therefore, for reentry, the isthmus long-axis would beexpected to most commonly align in parallel with muscle fiber direction,with the long block line forming during premature excitation aligningapproximately perpendicular to it and hence transverse to muscle fibers.This would tend to maximize slow propagation of the premature wave-frontsince it would then proceed primarily in the direction transverse tofiber orientation prior to its arrival at the isthmus formation area(factor 1 above; see FIGS. 23A-23Y). Also, presence of a greaterdensity, surface area, and/or increased severity of abnormal cells (upto some limiting value after which conduction proceeds too slowly or notat all) would be expected to increase the likelihood of reentry byincreasing factors 2-4 above, which would also slow propagation of thepremature wave-front. If factors 2-4 were sufficiently great to providethe necessary delay for breakthrough at the end of the prematureexcitation cycle, the reentry isthmus long axis could conceivably bealigned nearly transverse to muscle fibers (i.e., negligiblecontribution of factor 1, nonuniform anisotropic conduction^(1,10), forreentry induction) as has been observed in approximately 15% of canineinfarct experiments with monomorphic reentrant circuits². These samefactors 1-4 also act to slow conduction when the premature stimulationsite is within the area where the isthmus actually forms (centerstimulation as in FIGS. 23A, 23E, 23J, 23R, 23U), except that the delaydue to factor 4 above occurs immediately following application of thepremature stimulus pulse, rather than at the end of the prematureexcitation cycle.

When the activating wave-front arrives on the opposite side of theunidirectional arc, breakthrough will occur at the point where recoveryof excitability is first achieved, which will most likely be the placewhere the substrate properties are closest to normal epicardial tissue¹.Normal epicardial tissue is characterized by relatively rapid impulseconduction (˜1 m/s), and the electrogram deflection is narrow comparedwith abnormal epicardium¹. Hence as anticipated, the point of shortestelectrogram duration, on the order of 15-25 ms in this study, wasindicative of the breakthrough point as can be observed in FIG. 22B. Asdescribed elsewhere², more rapid conduction during tachycardia tended tooccur at all of the patchwork areas having relatively short sinus rhythmelectrogram duration, which supports the hypothesis that these areasactivate more normally than do other areas of the infarct border zone.Breakthrough across the arc of unidirectional block was oftensignificantly delayed upon arrival of the activation wave-front (by˜20-60 ms), which suggests that very slow conduction occurred as thewave-front impinged upon the block line, on an order that would be belowthe spatial resolution of the mapping system used for data acquisition(4-5 mm distance between recording sites). Other investigators haveobserved ultra slow conduction in myocardial tissue (conduction velocityof 1-2 cm/s)¹¹, which could account for the substantial delay that wasobserved to occur between arrival of the wave-front on the opposite sideof the unidirectional block and onset of reentry.

Although the sinus rhythm electrogram duration tended to be short withinthe area where the isthmus of the reentrant circuit formed (FIG. 22B),conduction there tended to be relatively slow during prematureexcitation (FIG. 22E), which was paradoxical to the behavior of otherareas of the border zone just described. However, two unique tissueproperties at this area of the border zone likely influences electrogramshape. Firstly, the surviving tissue tends to be thinnest at the regionwhere the isthmus forms^(1,12) so that little or no asynchronousactivation of underlying tissue would be anticipated to occur that couldact to expand the electrogram deflection. Secondly, although disruptionof gap junctional interconnections is prevalent throughout the areawhere the isthmus forms, this disruption tends to be relatively uniformfrom cell to cell³. Therefore, the properties of electricalinterconnection of the epicardial substrate in this region of the borderzone are relatively constant, so that presence of conductioninhomogeneities that could also act to expand the electrogram deflectionwould be expected to be negligible.

5. Clinical Correlates

Although clinical ventricular tachycardias can originate from intramuralreentry and focal mechanisms⁹, both contact¹³ and noncontact⁶ studiessuggest that substantial numbers of tachycardias are caused by reentrantcircuits that are mostly or entirely constrained to the endocardialsurface. Patients with unstable tachycardias and with multiple clinicaltachycardia morphologies are common, but these are the most difficult totreat using catheter ablation. Stevenson's group found that singlecatheter ablation lesions in human ventricular tachycardia were usefulto prevent recurrence of unstable tachycardias and multiple tachycardiamorphologies¹³. In their study, lesion placement was guided initially bysinus rhythm electrogram measurements (identification of low-voltageregions). This was followed by induction of ventricular tachycardia andfinal positioning of the catheter using the tachycardia recordings todetermine locations where pacing resulted in entrainment with concealedfusion. If ablation of infarct-related tachycardia could be guided bydelineation of the infarct region based on sinus rhythm electrogramsalone, it would be of clinically relevance, because haemodynamicstability would be maintained with successful ablation of unstable andmultiple morphology tachycardias¹³.

It the canine infarct study described herein, dual reentry morphologieswere inducible in 2 of 25 experiments. In the dual reentry morphologyexperiments, the functional arcs of block of each morphology mostlycoincided, both those forming during premature excitation and thoseforming during reentry (FIGS. 23K-23L). This result suggests that asingle ablation lesion may prevent recurrence of dual morphologies incanine model experiments, as in clinical studies^(13,14), and thereforethat the methodology has potential clinical application. This may beparticularly relevant since areas of lesion tend to be extensive wheneach of multiple reentry morphologies are separately ablated duringclinical therapy, which is not desirable because the risk ofcomplications, including damage to functioning myocardium, mayincrease¹³. Moreover, targeting of reentrant circuits by ablating thelocation of the estimated breakthrough point at the end of the prematureexcitation cycle, for any type of tachycardia, would have the addedbenefit of reducing lesion size, thereby also diminishing thepossibility of significant structural damage to the heart, compared withthe conventional approach of ablating across the entire width of thereentrant circuit isthmus. Finally, estimation of the stimulus sitelocation most likely to result in reentry induction, based on symmetryof the ends of the long functional arc of block estimated to form duringpremature excitation, would be useful when the reentry circuit iscomplex and induction of the tachycardia morphology is necessary toaccurately map the pathway.

Reentrant ventricular tachycardia in postinfarction human hearts tendsto be more complex and involve more layers than the two-dimensionalcanine heart model of reentry in the epicardium that was used for thisstudy^(9,13-14). Therefore, application of the methodology describedherein to clinical tachycardias may potentially yield significantlydifferent results. Electrogram duration measurements were made using anarbitrary amplitude threshold to delineate the contiguous time intervalassociated with local activation. Use of a different threshold couldalter the precise locations of regions with differing electrogramduration. Corroborating histologic analyses would be useful in futurestudies to correlate electrical activity, as measured by quantificationof electrogram shape, to presence of abnormal cellular coupling.

D. References For Fourth Series of Experiements

-   1. Wit A L, Janse M J. Basic mechanisms of arrhythmias. In: Wit A L    and Janse M J, eds. The ventricular arrhythmias of ischemia and    infarction. New York, N.Y.: Futura; 1993:1-160.-   2. Ciaccio E J, Costeas C A, Coromilas J et al. Static relationship    of cycle-length to reentrant circuit geometry. Circulation, 2001;    104:1946-1951.-   3. Peters N S, Coromilas J, Severs N J et al. Disturbed connexin43    gap junction distribution correlates with the location of reentrant    circuits in the epicardial border zone of healing canine infarcts    that cause ventricular tachycardia. Circulation 1997; 95:988-996.-   4. Ciaccio E J, Tosti A C, Scheinman M M. Relationship between sinus    rhythm activation and the reentrant ventricular tachycardia isthmus.    Circulation 2001; 104:613-619.-   5. Dillon S M, Allessie M A, Ursell P C et al. Influences of    anisotropic tissue structure on reentrant circuits in epicardial    border zone of subacute canine infarcts. Circulation Research 1988;    63:182-206.-   6. Schilling R J. Peters N S. Davies D W. Feasibility of a    noncontact catheter for endocardial mapping of human ventricular    tachycardia. Circulation 1999; 99:2543-52.-   7. Spach M S, Miller W T III, Dolber P C et al. The functional role    of structural complexities in the propagation of depolarization in    the atrium of the dog. Circulation Research 1982; 50:175-191.-   8. Ciaccio E J. Dynamic relationship of cycle length to reentrant    circuit geometry and to the slow conduction zone during ventricular    tachycardia. Circulation, 2001; 103:1017-1024.-   9. Pogwizd S M, McKenzie J P, Cain M E. Mechanisms underlying    spontaneous and induced ventricular arrhythmias in patients with    idiopathic dilated cardiomyopathy. Circulation 1998;98:2404-14.-   10. Gardner P I, Ursell P C, Fenoglio J J Jr. et al.    Electrophysiologic and anatomic basis for fractionated electrograms    recorded from healed myocardial infarcts. Circulation    1985;72:596-611.-   11. Rohr S. Kleber A G. Kucera J P. Optical recording of impulse    propagation in designer cultures. Cardiac tissue architectures    inducing ultra-slow conduction. Trends in Cardiovascular Medicine.    1999; 9:173-9.-   12. Scherlag B J, Brachman J, Kabell G et al. Sustained ventricular    tachycardia: common functional properties of different anatomical    substrates. In Zipes D P, Jalife J, eds. Cardiac electrophysiology    and arrhythmias. Orlando Fla.: Grune and Stratton; 1985:379-387.-   13. Soejima K, Suzuki M, Maisel W H et al. Catheter ablation in    patients with multiple and unstable ventricular tachycardias after    myocardial infarction: short ablation lines guided by reentry    circuit isthmuses and sinus rhythm mapping. Circulation.    2001;104:664-9.-   14. Downar E, Saito J, Doig J C, et al. Endocardial mapping of    ventricular tachycardia in the intact human ventricle. III. evidence    of multiuse reentry with spontaneous and induced block in portions    of the reentrant path complex. JACC 1995;25:1591-1600.

1. A system for identifying and localizing a reentrant circuit isthmusin a heart of a subject during sinus rhythm, comprising: (a) aninterface for receiving electrogram signals from the heart during sinusrhythm via electrodes; (b) processing means for creating a map based onthe received electrogram signals, and determining, based on the map, alocation of the reentrant circuit isthmus in the heart; and (c) adisplay adapted to display the location of the reentrant circuitisthmus, wherein activation times of the received electrogram signalsare arranged based on a position of the respective electrodes.
 2. Thesystem of claim 1, wherein the activation times are measured from apredetermined start time until reception of a predetermined electrogramsignal.
 3. The system of claim 1, wherein the map includes isochronesfor identifying electrogram signals having activation times within apredetermined range.
 4. The system of claim 1, wherein a centerreference activation location on the map is determined by averaging anelectrode coordinate position of a predetermined number of electrogramsignals selected based on an activation time.
 5. The system of claim 4,wherein measurement vectors originating from the center referenceactivation location and extending outward on the map are defined and areused to designate the electrodes located along the measurement vectors.6. The system of claim 5, wherein the electrodes assigned to ameasurement vector are chosen according to a distance from themeasurement vector.
 7. The system of claim 5, wherein the electrodesassigned to a measurement vector are a subset of the electrodes chosenaccording to a distance from the measurement vector.
 8. The system ofclaim 5, wherein a primary axis vector having one of an activationgradient value within a predetermined range and a highest activationuniformity value within a predetermined range is selected from themeasurement vectors, and the primary axis vector indicates a location ofthe reentrant circuit isthmus.
 9. The system of claim 8, wherein theactivation uniformity value is a coefficient of linear regression. 10.The system of claim 8, wherein the activation uniformity value is acoefficient of non-linear regression.
 11. The system of claim 8, whereinthe activation uniformity value is a variance in activation times alonga selected measurement vector.
 12. The system of claim 8, wherein theactivation uniformity value is a measure of variability along a selectedmeasurement vector.
 13. The system of claim 8, wherein the activationgradient value is a slope of a linear regression line.
 14. The system ofclaim 8, wherein the activation gradient value is a slope of anon-linear regression line.
 15. The system of claim 8, wherein theactivation gradient value is a mean absolute difference in activationtimes along a selected measurement vector.
 16. The system of claim 8,wherein the activation gradient value is a difference along themeasurement vector.
 17. A method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising the steps of: (a) receiving electrogram signals from theheart during sinus rhythm via electrodes; (b) creating a map based onthe received electrogram signals, including arranging activation timesof the received electrogram signals based on a position of therespective electrodes; (c) determining, based on the map, a location ofthe reentrant circuit isthmus in the heart, including finding a centerreference activation location on the map by averaging an electrodecoordinate position of a predetermined number of electrogram signalsselected based on an activation time, defining measurement vectorsoriginating from the center reference activation location and extendingoutward on the map, the measurement vectors used to designate theelectrodes located along the measurement vectors, and selecting from themeasurement vectors a primary axis vector having one of an activationgradient value within a predetermined range and a highest activationuniformity value within a predetermined range and where the primary axisvector indicates a location of the reentrant circuit isthmus; and (d)displaying the location of the reentrant circuit isthmus, wherein theprimary axis vector has a mean electrogram activation duration in apredetermined range.
 18. A method for identifying and localizing areentrant circuit isthmus in a heart of a subject during sinus rhythm,comprising the steps of: (a) receiving electrogram signals from theheart during sinus rhythm via electrodes; (b) creating a map based onthe received electrogram signals, including arranging activation timesof the received electrogram signals based on a position of therespective electrodes; (c) determining, based on the map, a location ofthe reentrant circuit isthmus in the heart, including finding a centerreference activation location on the map by averaging an electrodecoordinate position of a predetermined number of electrogram signalsselected based on an activation time, defining measurement vectorsoriginating from the center reference activation location and extendingoutward on the map, the measurement vectors used to designate theelectrodes located along the measurement vectors, and selecting from themeasurement vectors a primary axis vector having one of a meanelectrogram activation duration within a predetermined range, anactivation gradient value within a predetermined range and a highestactivation uniformity value within a predetermined range and where theprimary axis vector indicates the location of the reentrant circuitisthmus; and (d) displaying the location of the reentrant circuitisthmus.